Captain Sisko and the other Federation senior officers that had been stationed at Deep Space Nine were assigned with the Defiant to Starbase 375. They devised a plan to destroy the main Ketracel White storage facility in the Alpha Quadrant--without Ketracel White, the Jem'Hadar would no longer be obedient to the Founders. To infiltrate Cardassian territory, Sisko and his crew were given a repaired Jem'Hadar ship which the Federation had found crashed on a Gamma Quadrant planet a year before. Upon arrival to the facility, Chief O'Brien transported a bomb along with empty Ketracel White canisters into the main complex. Before their ship could escape, the facility's shields went up, trapping the ship inside. The bomb exploded as planned, destroying the facility, and the knocking out the shields. Their Jem'Hadar ship went to warp to avoid the blast, but wasn't completely successful, and the warp drive was damaged beyond repair. They crashed in the ocean of a barren planet in Cardassian space, and Jadzia was critically injured, though Doctor Bashir was able to stabilize her condition. Garak and Nog went searching for food and water, and were taken prisoner by a group of Jem'Hadar who had also crash landed there. They took them to their Vorta, who was deathly ill, and Garak told him that they had a Doctor. The Jem'Hadar traded Garak and Nog for Captain Sisko and Doctor Bashir, who saved the Vorta's life. When the Jem'Hadar were gone, the Vorta told Sisko and Bashir that he had only one canister of Ketracel White left for them, and when that was gone, they would be uncontrollable, killing everyone, lastly themselves. He told Sisko he was going to order the Jem'Hadar to attack their camp the next morning, and wanted Sisko's people to be ready and kill them all in order to save everyone else. Seeing no other alternative, Sisko reluctantly agreed, and followed through with his promise. Chief O'Brien found the Vorta's broken communications equipment, repaired it, and they were saved from the planet by Worf who received the signal a short time later. The Vorta was taken as a prisoner of war.
Admiral Ross of Starfleet Command had found the reason for the Dominion's dominance in the war--they had been using a massive sensor array to monitor all ship movements across five sectors of space. Jadzia took the Defiant on a mission to destroy the array, and was successful. Meanwhile, on Terok Nor (the Cardassians of the Dominion had given the station back its old name) Kira, Odo, Rom, Quark, Jake, and Leeta (Rom's Bajoran wife) had formed a small resistance cell against the station's new commanders. Quark learned that Gul Damar (Gul Dukat's second-in-command) had found a way to disable the mine field blocking the wormhole using the station's deflector array. Kira devised a plan to stop him: Odo would run a security diagnostic giving Rom a five minute opportunity to disable the array without being detected. However, Odo was distracted by the Female Changeling, who told him the Great Link forgave him for killing one of his people, and Odo and she physically linked together--something the Changelings always did to share thoughts, which Odo had been neglected his whole life. The array wasn't disabled, and Rom was caught because the security diagnostic hadn't been run. Kira called Odo the enemy for not fulfilling his duty to them. Too overcome with his experience linking with the Female Changeling, Odo didn't seem to care about Kira or his duty anymore. Rom had been sentenced to execution by the Dominion, and so Kira went to Ziyal (Gul Dukat's daughter that she had helped rescue from a Breen mining slave camp a few years before) and asked her to try and convince her father not to go through with the execution. Dukat refused to listen to her, and she expressed to him how much she hated him for leading the war. Even though Weyoun pestered him about it non-stop, Dukat became more interested in reconciling with Ziyal than stopping the Federation-Klingon-Romulan armada Captain Sisko and Admiral Ross were rallying at Starbase 375 to retake the station. Later, Odo snapped back into the reality of things and apologized to Kira, but she didn't accept it. Gul Damar was days away from taking down the mine field, but the armada growing at Starbase 375 was already on its way to retake Terok Nor. With the Dominion aware of Sisko's plan to retake the station, the Federation-Klingon armada would have to get past a wall of over one thousand Cardassian and Jem'Hadar ships blocking the way to Terok Nor, and retake the station before Gul Damar was able to disable the minefield. Leading the Federation-Klingon fleet with the Defiant, Sisko--knowing that the Jem'Hadar would never deviate from their sense of order--gave the order to attack only the Cardassian vessels. He hoped to provoke them into breaking their formation; punching a hole in the wall which one of the Federation or Klingon ships could slip through. His plan worked, and being at the front of the pack, the Defiant was the ship to slip through to Terok Nor, as the rest of the fleet remained in a titanic battle. On the station, Odo rejoined the Dominion resistance in cutting off the power to Terok Nor's weapons. However, they were too late; Damar had already destroyed the minefield. The wormhole became open to a flotilla of Dominion ships which were on their way through to the Alpha Quadrant. Upon arrival to Terok Nor, Sisko turned immediately into the Bajoran Wormhole to meet the armada, when he had a vision from the Prophets. He was able to communicate with them, and begged them to stop the Dominion fleet for the sake of the Bajoran people, who had formed their entire religion around them. The Dominion ships disappeared, apparently destroyed, and the Defiant exited the wormhole to find two hundred Federation ships attacking Terok Nor. The Dominion was forced to give up the station. During their evacuation, Ziyal refused to leave with her father Dukat, and was killed by Damar, who then escaped to become the new Cardassian leader. Gul Dukat was captured when the Federation retook Terok Nor, once again named Deep Space Nine.
Jem'Hadar soldiers, Vorta clones, and Dominon ships were being generated to quickly for the Federation to keep up in the war. In order to win, Sisko knew they needed new allies: the Romulans. Despite signing a non-aggression treaty with the Dominon, Sisko was convinced the Dominion would eventually invade Romulus (the Romulan home world) anyway. He asked Garak to retrieve evidence of that fact from one of his Cardassian friends, but they were all killed within a day of Garak having spoke to them. They decided to create false evidence, and a holographic program showing a meeting of Damar and Weyoun (the Cardassian and Dominion leaders) discussing plans to invade Romulus was created, and saved to a fake Cardassian data rod. After viewing the program, a Romulan leader wanted to inspect the rod to ensure it was authentic. Sisko and Garak were shocked when he was able to tell the rod was a fake. After departing the station, the Romulan leader's ship exploded. Evidence showed it was an act of the Dominion, but it had really been Garak, who planted to bomb to ensure the plan worked. It did. The Romulan Empire declared war on the Dominon, and an infuriated Sisko had to decide he could live with his wrong doings if it would help the Federation win the war.
In another vision from the Bajoran Prophets, Captain Sisko was told that the "Reckoning" must begin. According Bajoran prophecies, the Reckoning was to be a time when a Prophet would battle a Pah-Wraith (an evil Prophet that had been banned from the Celestial Temple). Kai Winn said that if the Prophet won, it would bring in Bajor's "Golden Age". She also informed Sisko that an ancient tablet with writing written in Ancient Bajoran had been found in the lost city of B'hala, and Sisko went to Bajor to have a look. Dax suggested bringing the tablet back to DS9 for further examination, and later that night Sisko instinctively destroyed it. A strange vortex of violent energy was released--a Pah-Wraith! The next day the station was evacuated. Major Kira had become possessed by a Prophet, and Jake by the Pah-Wraith released from the tablet. Before their battle began, Dax rigged the station's conduits with radiation that could be released to free Kira and Jake of their possessors, if the fight threatened one of their lives. Sisko refused to use it, but Kai Winn did not. During the battle, she slipped away and activated the radiation before one of the combatants could be defeated. When she was escorted off the station the next day, Kira told the Kai that she may have defied the Prophets so drastically by discontinuing the fight, that they would never forgive her.
Dukat escaped from the hold of the Federation, and returned to Cardassia Prime claiming that he had the answer to the Dominion's winning the war. He opened a bizarre case, releasing a Pah-Wraith which suddenly manifested in his body. Meanwhile, Sisko and the Defiant joined a Federation-Klingon-Romulan offensive strike: the invasion of the Cardassian Chin'toka System. Dax was left in charge of Deep Space Nine and was in the station's Bajoran Shrine when the possessed Dukat appeared before her. Using a magical energy beam shot from his hand, he smacked Dax out of the way of an orb she was standing in front of. Dukat destroyed the orb, and then disappeared. The Defiant returned from a great victory to find that Dax had been killed by Dukat's evil blow. The remaining orbs went dark, and the wormhole collapsed. Feeling that he had failed in his duties as the Emissary and as a Starfleet Captain, Sisko returned to Earth on an indefinite leave of absence.