Mass Effect: Andromeda begins in November 2185, between the events of Mass Effect 2 and Mass Effect 3. The four Citadel Council races and the Quarians are planning to populate new home worlds in the Andromeda Galaxy as part of a strategy called the Andromeda Initiative. Each Council race sends 20,000 citizens on a one-way, 600-year journey to Andromeda aboard their own transportation vessel, called an Ark, and selects a leader, known as a Pathfinder. The Quarians and the final fifth ark would be the largest containing 5 different races with 100,000 colonists. It's launch was delayed due to the complexity of integrating the various biomes on the Ark, launching some time in 2186 and would arrive last.  Once the Arks arrive, they help complete the Nexus, a space station that serves as a center of government and diplomacy, a living area, as well as a base of operations for the Pathfinders. As Headquarters of the Andromeda Initiative, the Nexus is a massive space station designed to anchor the returning arks, process resources, and support colonists before their departure to new worlds. The Nexus carried a crew of its own comprised of 100,000 colonists comprised of all four of the Council races and about 8000 Krogan.

 In 2819, following a 634-year journey aboard the Ark Hyperion awakens in the Heleus Cluster of the Andromeda Galaxy. Alec Ryder,  humanity's Pathfinder, tasked with finding a new home for the species awakens to find that the mission has gone terribly wrong. Alec's second-in-command, Cora Harper, assemble a team to investigate the problem.

The Hyperion has struck a dark energy cloud called the Scourge, temporarily knocking out its power and sending one of Alec Ryder's two adult children into a coma. Pathfinder Alec Ryder, Ryder's father, informs the remaining Ryder  and Cora Harper that the planet they were sent to scout may no longer be viable for colonization. Alec, Ryder, Cora, and Liam Kosta head down to the planet, coming into contact with a hostile alien race, the kett, as well as strange structures from a synthetic alien race, the Remnant. Ryder and Alec find a terminal inside an alien monolith, which Alec activates in an attempt to stabilize the lightning storm-stricken planet. A large blast throws the two off the elevated platform, damaging Ryder's helmet and exposing Ryder to the toxic atmosphere. Alec saves Ryder by giving Ryder his helmet, sacrificing his own life. Ryder is later revived and merged with the artificial intelligence SAM, learning that Alec has made Ryder the new Pathfinder.

Hyperion reaches the Nexus, finding it incomplete and with no other Ark in sight. The crew learn from Nexus leadership that all of the worlds in Andromeda have become inhospitable, and that the Initiative has been stranded upon arrival, suffering from civil unrest and a supply shortage. As humanity's new Pathfinder, Ryder is tasked with finding a suitable world to colonize, as well as uncovering the fates of the other Arks. Ryder is also assigned a spaceship, the Tempest, piloted by Kallo Jath and accompanied by Vetra Nyx.

Ryder's first stop on the search is Eos, a desert planet plagued by radiation, where Nakmor Drack and Pelessaria B'Sayle (Peebee) join the crew. With SAM's help, Ryder unlocks a Remnant vault, which houses a terraforming system that gradually repairs the planet's ecosystem to more hospitable levels. The planet's newly improved viability allows Ryder to establish Andromeda's first successful outpost. Ryder also discovers a star chart pinpointing the location of other worlds that might hold similar structures. It is deduced that these worlds could sustain the Initiative.

On the way to another system, the Tempest runs into the kett fleet, and is forced to escape through the Scourge, suffering significant damage. The ship lands on the planet Aya, coming into contact with a new alien species, the angara, who are mounting a resistance against the kett. Ryder proves the Initiative's good intentions by aiding the angara on two other planets, in addition to recruiting a member of their species, Jaal Ama Darav, to the Tempest's crew. Ryder also rescues high-ranking angara Moshae Sjefa from a kett facility, discovering in the process that the kett have been turning the angara into more kett through a genetic modification process known as "exaltation". The Moshae takes Ryder to Aya's vault, learning that the kett leader, the Archon, is chasing an object called Meridian, which can control all vaults and, by extension, the worlds that they are connected to. Ryder, anxious to stop the kett, tracks down their flagship and discovers that the kett have captured the Salarian Ark and have been experimenting with various Initiative species. Ryder frees the ark and learns the location of Meridian.

Ryder then proceeds to the presumed location of Meridian, which is revealed to be an ancient Remnant city. Ryder discovers that Meridian, a Dyson sphere-like construct, was taken away from the city, disconnecting the vaults and rendering the planets uninhabitable.^[46] The Archon launches an attack on Hyperion, severing SAM from Ryder, while also capturing Ryder's sibling, whose SAM implant he intends to use in order to take over Meridian. Ryder manages to activate the Remnant fleet and, together with other allied forces, makes an assault on the kett fleet guarding Meridian. The Ryder twins work to defeat the kett, eventually disconnecting the Archon from Meridian's system and killing him in the process. Ryder is hailed as a hero, having activated Meridian and made the cluster more suitable for settlement. Hyperion, after crash-landing onto Meridian, settles on the planet as humanity's new home.

In a post-credit scene, the Archon's second-in command, Primus, is seen observing Meridian, hinting at a possible future threat.