On June 21, 2028, chaos erupts in Los Angeles due to a riot protesting the privatization of water, highlighting the struggles of everyday people to afford basic necessities. Seizing the opportunity presented by the turmoil, a crew of four criminals — brothers Sherman and Lev, along with misfits Buke and P-22 — plan to rob a bank. As they attempt to breach the vault, they shift tactics, realizing they can instead loot the belongings of their hostages. These hostages are likely to be wealthy individuals sending their staff to safeguard their valuables amidst the rioting.
In a twist of irony, Lev swipes a fancy pen from one of the male hostages, despite a warning not to do so. Their escape is abruptly interrupted as they encounter police officers, resulting in a deadly exchange that leaves P-22 dead and both Buke and Lev critically injured. In a desperate bid for help, Sherman contacts Jean "the Nurse" Thomas (Jodie Foster), the manager of the Hotel Artemis, a unique establishment catering solely to criminals in need of medical attention.
Upon their arrival at the hotel, conditions are tight: only paying members are admitted, leaving Buke outside at the mercy of Everest (Dave Bautista), the Nurse's assistant. Inside, guests are referred to by their suite names — Sherman takes on the moniker Waikiki, while Lev is dubbed Honolulu. Other guests include Acapulco (Charlie Day) and Nice (Sofia Boutella).
Tensions escalate when Crosby Franklin (Zachary Quinto), a notorious criminal, alerts the Nurse that his father, Orian "The Wolf King" Franklin (Jeff Goldblum), is on his way and desperately needs immediate care. Waikiki reconnects with Nice and discovers that the pen Lev stole is, in fact, a mobile safe containing diamonds that belong to the Wolf King. This revelation sets off a chain of events filled with danger, as the Wolf King is known for ruthlessly eliminating anyone who crosses him.
The stakes rise further when a wounded police officer named Morgan (Jenny Slate) appears at the hotel, seeking treatment. Ignoring Everest's warnings, Thomas ventures out to assist Morgan, only for them to be confronted by the riotous mob. Thankfully, Everest intervenes just in time to save them both. The connection between Thomas and Morgan runs deep, as she once knew Morgan from a time before tragedy struck her life — her son's death fueled her descent into alcoholism and her subsequent turn to running the Artemis.
Within the confines of the Artemis, the tension builds as Acapulco tries to escape via helicopter, only to be ambushed by Nice, who seeks to eliminate the Wolf King. Meanwhile, Everest secretly leads Morgan out, while Waikiki uses a 3D printer to create a weapon for their defense. The complex web of loyalties and betrayals deepens when both the Wolf King and Crosby Franklin arrive, leading to an intense situation wherein Thomas must navigate her need for vengeance and the duties of her role at the Artemis.
During an unexpected turn of anesthesia, the Wolf King, unaware of the repercussions, reveals damning information about Thomas’ son, pushing her towards a dangerous choice fueled by anguish. The eventual explosion caused by Nice's machinations culminates in a deadly aftermath where alliances shift, and lives are lost. Waikiki finds himself grappling with the consequences of Nice's actions and its tragic toll on his brother, leading to a violent confrontation with Acapulco.
As chaos envelops the Artemis, and Crosby’s crew begins to breach the hotel’s defenses, Waikiki and Nice must cooperate to escape. In a final act of desperation, Waikiki trades the stolen pen — a cache of wealth that could secure their safety — only to confront Crosby, who forces Thomas into a deadly dilemma. In a haunting conclusion, Thomas finally confronts her fears and plows through her past, finding a modicum of peace despite the violence surrounding her.
Just as it seems all hope is lost, a glimmer of possibility remains. Thomas, intent on a new path, contemplates reopening the Artemis to lend help once more. As she walks through the chaotic streets of Los Angeles, a flicker of resilience ignites within her. Meanwhile, Everest, triumphant in battle, dons his nurse's badge, illuminating the Hotel Artemis' sign as a sign of renewed purpose.
In a heart-pounding mid-credits scene, the fate of Nice is left ambiguous, hinting that she may have survived, leaving audiences on the edge of anticipation.
