On June 7, 2022, Maddon was fired and Phil Nevin was named the interim manager for the remainder of the season after they had lost twelve games in a row, tying a record set by the 1988 team.

The National League will adopt the designated hitter full-time, a draft lottery will be implemented, the postseason will expand from ten teams to twelve, and advertising patches will appear on player uniforms and helmets for the first time.

[10] The Angels opened the season on April 7 at home against the Houston Astros in front of a crowd of 44,723, losing 3–1 after Shohei Ohtani pitched 4.2 innings and gave up 1 run.

[12] On May 10, Reid Detmers became the ninth player in Angels history to throw a no-hitter, doing so against the Tampa Bay Rays in a 12–0 win.

In the bottom of the 8th, Angels third baseman Anthony Rendon took the first left-handed at-bat of his career and proceeded to hit a two-run home run off Brett Phillips, a position player pitching, to make the score 12–0.

On May 14, closer Raisel Iglesias gave up a walk-off home run to Athletics outfielder Luis Barrera, his first blown save since July 28, 2021.

[12] On June 6, the Angels fell 1–0 to the Red Sox, bringing their losing streak to 12 games, tied for the worst in franchise history.

[14] On June 8, the Angels lost their 14th straight game, setting a new record for longest losing streak in franchise history.

[12] On June 11, Jared Walsh hit for the cycle in an 11–6 win over the New York Mets, becoming the ninth player in Angels history to do so.

[18][12] On June 26, Mariners batter Julio Rodríguez was hit by a pitch from Angels opener Andrew Wantz in the first inning.

During his minor league stint, pitching instructor Buddy Carlyle helped Detmers tweak an error with his mechanics during a videotape session.

[22] Ohtani was selected as both a designated hitter and pitcher for the second consecutive season, and fans voted him as the starting DH over Yordan Alvarez.

He followed Sandy Koufax and Mike Fiers as the third player in MLB history to throw a no-hitter and immaculate inning in the same season and became the first to do so as a rookie.

Shortly after, the Angels completed another trade with the Phillies, sending veteran starting pitcher Noah Syndergaard in exchange for former top draft pick Mickey Moniak and prospect Jadiel Sanchez.

[25] On August 23, Angels owner Arte Moreno formally announced that he would explore a possible sale of the franchise with preliminary media reports saying the hypothetical change in ownership was likely.

At the time of the announcement, the Federal Bureau of Investigation was conducting a corruption probe for the quashed stadium property sale that prompted Anaheim mayor Harry Sidhu's resignation.