The fourth and final season opens when out of the ashes of humanity's nuclear war, Night Eternal has begun. Haunted by the atrocities committed by his son, Eph abandons NYC for Philadelphia. His solitude is cut short when he encounters new fighters who rekindle his drive to fight back. Tasked by Setrakian, Fet and Quinlan search for a new means of stopping the Master.

Imprisoned as a subject in a strigoi breeding program, Dutch is desperate to escape and find Setrakian. Gus recruits his cousin for the inside job that will put his gang at the top of the new world's underground economy, but Creem is suspicious of his business partner's ambitions and a CDC team investigates the outbreak of a mysterious illness that mirrors vampirism.

Quinlan and Fet discover that stealing a nuclear warhead isn't easy when they encounter an unexpected enemy. Eph and Alex concoct a new weapon to use against the strigoi. Frustrated with his seclusion, Zack discovers a love interest.

Dutch is forced to make a deal with Desai while she plots to escape a strigoi breeding facility. Eph and Alex seek to uncover the dark secrets behind the Partnership's new plan but face the repercussion of their last attack. Gus and Creem face off against a gang encroaching on their turf.

Fet and Quinlan are hot on the trail of a convoy carrying their prized nuclear weapon. Eph and Alex search for clues to uncover the Master's plan for the ultimate fate of the human race. Dutch is trapped by a familiar enemy, yet encounters an old friend as well.

Fet and Quinlan have to figure out how to get the nuclear bomb back to New York, while a desperate Eichhorst draws near. Love... struck Zack tries to learn more about his new crush, but makes a devastating discovery.

His health failing, Setrakian ignores Eph's warnings, pushing himself to the limit in his quest for victory and revenge. Fet and Quinlan race back to Manhattan, while the Master seals off the city and prepares to eliminate them all.

Reeling from loss, our heroes regroup. To defeat the Master, they must locate him first. Our heroes devise a new plan to track him through human collaborators, beginning at the blood farm with someone Dutch knows all too well.

An unexpected guest brings old conflicts to the surface, dividing our heroes, threatening the group's trust. With questionable new intel in hand, they launch a make... or... break final assault on the Master.

Quinlan devises a desperate plan, but the costs are enormous. Eph wrestles with his conscience, Fet undertakes a sleeping mission, and Dutch and Gus dig in for battle as humankind makes its final stand against the Master and his Strain.