While Black Ops 4 doesn't have a traditional campaign, it does have a story, told via the Combat Immersion Training Simulator.
In 2043, a botched mission caused the disappearance and presumed death of Jessica Mason-Green, granddaughter of legendary CIA Black Operative Alex Mason. 2 years later, Jessica's elder sister Dr Savannah Meyer recruits ten of the world's leading soldiers and operatives to hunt down the people responsible for Jessica's disappearance. Savannah introduces them to their AI coach while in the Combat Immersion training simulator, her grandfather's best friend Sgt. Frank Woods. Little do they know, they are being set up for something even worse...
Donnie 'Ruin' Walsh talks with his friend Erin 'Battery' Baker about the night their squadmate Jessica was captured 2 years prior. He notes that it was odd that they got away while she didn't even when their marks had superior firepower and numbers. Battery believes it to be a mere coincidence, until she hears a recording Ruin received telling them to watch their backs, as everything they know is wrong. Ruin later receives a message from the mysterious ally, telling him he has been betrayed and mercs are converging on his position. He bails, knocking most of them away with a Grav Slam, and heads to a safehouse. There, he discovers to his shock and horror that not only is Jessica alive, but that Savannah was the one who tried to have her killed.
Turns out, Savannah had been researching a way of bringing people back from the dead, as Archetypes. In order to finance her off-the-books venture, she turned to Cordis Die leader Raul Menendez for the financial aid, as well as procuring samples. After reviving several, including Frank Woods and her own grandfather Alex, Jessica calls her out on her unethical research and threatens to blow the whistle on the whole operation. In turn, Menendez tells Savannah that Jessica threatens the entire project, and that the threat must be removed.
Jessica meanwhile realizes her mistake, and tells Alex that she needs to straighten the whole mess out. Savannah tells them that she is in way over her head with Raul and that Jessica's safety is more important than her research. However, at the mention of Lucy, Jessica flies off into a rage, struggling with Savannah until a gunshot is heard. Jessica has been shot, and is dying right in front of them.
Later, Alex is in an unknown place, demanding to know where his granddaughter is to his captors. Meanwhile, Menendez blackmails Savannah into relinquishing full control over Project Blackout to him, in exchange for him not turning her in for murder. It is revealed that Jessica was brought back using the project, with false memories planted to ensure she didn't remember. However, the shot she received upon her capture triggered flashbacks of her first death, and while her squad escaped, she was able to kill all her captors and go dark. Menendez reveals that Jessica is alive and has been compromising the Specialists, and responds that they need to eliminate them all before they blow the whole project. Meanwhile, Frank is tasked with reprogramming Alex using the Ascension numbers to follow new orders. This even extends to resurrecting Victor Reznov to make Alex more compliant. He reveals that Reznov was the first Archetype selected, due to his history in WW2.
Project Blackout is revealed to be a means of creating sites all around the world where soldiers can fight and release their bloodshed, the crimson cancer, on an even playing field. Men and women from all walks of life can fight to the death and be reborn, again and again. Woods realizes he's been played by Savannah, to turn Alex into her own hitman, out to kill his own granddaughter, so abducts him and tells him he's working on a way to fix things. Within the Blackout...
