Eleven months after the chiral network connected the United Cities of America, Sam Porter (Norman Reedus) lives a secluded life in Mexico with Lou. Fragile (Léa Seydoux) arrives at his home and informs him that she has formed a new company, Drawbridge, which has been contracted by the UCA to extend the chiral network to Mexico. Fragile asks Sam to activate the chiral network terminals BRIDGES left behind in Mexico, just like he did in the United States. Sam agrees on the condition that both he and Lou be pardoned by the UCA, and because his route will take him to a lab where Deadman (Guillermo del Toro/Jesse Corti) works.

He leaves while Fragile takes care of Lou. Arriving at the lab, Sam views a recording left behind by Deadman explaining that he had discovered an anomaly in southern Mexico dubbed a "plate gate", which acts as a portal to Australia where other Death Stranding survivors reside. In addition, Deadman found out that for unknown reasons, Lou was assigned a BB ID number that belonged to an already decommissioned BB, meaning that Lou is not actually registered in the UCA's system. Furthermore, Deadman reveals his lifespan is running out, and has decided to travel to his Beach. Sam returns home to discover that it had been assaulted by an unknown armed group.

While Fragile managed to survive, Lou was killed. One month later, Sam continues to grapple with Lou's death when he is invited by Fragile to board her ship, the DHV Magellan, to travel through the plate gate so they can link Australia to the chiral network. On board, he meets Fragile's crew, Tar Man (George Miller/Marty Rhone)[c] and Dollman (Fatih Akin/Jonathan Roumie),[d] Drawbridge's mysterious benefactor, Charlie, and the leader of the Automated Public Assistance Company (APAC), the President (Alastair Duncan). The President explains that by connecting all of Australia to the chiral network, it should activate additional plate gates that will be able to connect all of the world's continents together.

Drawbridge members Rainy (Shioli Kutsuna) and Heartman (Nicolas Winding Refn/Darren Jacobs)[e] join the crew. Sam commences his mission, but is impeded by the apparent return of Higgs (Troy Baker), who commands an army of "ghost mechs" that terrorize the Australian survivors. In addition, Sam is drawn into "tarfall" anomalies where he is forced to fight a spectral soldier named Neil Vana (Luca Marinelli) who apparently has connections to Lou. After his first encounter with Neil, Sam recovers a chrysalis containing a girl Fragile decides to name Tomorrow (Elle Fanning). Sam is able to defeat Neil permanently.

Neil gives him a memory device left behind by Sam's late wife Lucy (Alissa Jung). The data inside explains that Lou is actually Sam's daughter who was thought killed along with Lucy in a voidout. As the daughter of a repatriate, Lou was secretly abducted by BRIDGES and designated BB-00, the very first Bridge Baby. However, for reasons unknown, Lou was put into storage until Sam came across her. Neil was a smuggler who helped smuggle braindead pregnant women from Mexico into the UCA to meet their demand for BBs.

He happened to be a childhood acquaintance of Lucy and attempted to help her and Lou escape from BRIDGES. Meanwhile, Higgs lays siege to the final network hub needed to complete the Australian chiral network. Sam and Drawbridge fight their way through Higgs' mechs and activate the hub, completing the chiral network. The President betrays Drawbridge, revealing that he is in fact an amalgamation of four thousand human souls connected to APAS. He explains that he intends to use the expanded chiral network to forcibly seclude all humans away in their Beaches to completely negate the risk of encountering BTs, thus protecting them from the Death Stranding.

He adds that he brought Higgs back and provided him the ghost mechs to act as a threat that would force Australia to adopt the chiral network for protection. Charlie then reveals himself as Die-Hardman (Tommie Earl Jenkins), and explains he was already aware of the President's plans and secretly reprogrammed Sam's Q-Pid so that The President can be disconnected from APAS and the chiral network, removing his threat to humanity.