The upcoming PlayStation 4 title features a host of famous faces besides, including Mads Mikkelsen, Margaret Qualley, Léa Seydoux, Lindsay Wagner and Guillermo del Toro — all of whom appear in the stunning clip.
In the game Reedus plays Sam, who is sent to another world — described as an "upside-down world submerged in water" by IGN — and can come back and forth between them, with actions in one affecting the other.
Instead of resetting to the point of death — as has been the case since the dawn of video games — the player continues playing in the "underworld" for a time before returning to the world of the living.
The 8-minute trailer shows a younger Reedus navigating both open worlds, protecting a pre-birth baby with umbilical cord still attached inside a self-contained capsule.
The title of the game refers to cetacean stranding, the unexplained phenomenon of whales and dolphins stranding themselves on beaches.
Fans have vented frustration and the length of time it has taken for the finished product to arrive; but designer Hideo Kojima is confident the new mechanics introduced in the game will be worth the wait.
"A lot of people have been telling me, 'You're crazy like Stanley Kubrick... like David Lynch,' and I'm honored," he said, "but these are all elements that play into the game design, and they do come together and they're in line."
The much-anticipated game is the famed designer's first since he split from Konami in 2015.
"Death Stranding" is set for release on PlayStation 4 in November, and on PC the following year.