CITY were allowed to select 5 players from a list of 23 teams as part of building out their inaugural roster in the 2022 MLS Expansion Draft.

After going down 2–1, St. Louis City SC got second-half goals from Jared Stroud (78’) and João Klauss (86’) to come from behind and earn their first win as a franchise, 3–2.

A quick Timbers goal to start the game put St. Louis City SC behind 1–0, but Jared Stroud tied it up in first half stoppage time (45+1’).

Goals from Niko Gioacchini (34’), João Klauss (45+3) and Tomáš Ostrák (68’) led to a 3–0 win — St. Louis City SC's 4th straight, and first Clean Sheet in franchise history.

[9] Coming home for April Fools' Day, St. Louis City SC had the tough task of breaking apart Minnesota United's low block system.

Despite a flurry of an attack at the end of the game and a great chance on goal by Sam Adeniran, Minnesota held on to give St. Louis City SC their first loss on the season.

[11] What many penciled in as St. Louis City SC's first true test of the season came on Matchday 7 at Seattle Sounders FC the following week, Apr 8.

At the time, both teams had led the Supporters Shield race at one point in the season with St. Louis City SC carrying a 5–2–0 record, while Cincy came in undefeated at 5–0–2.

Cincy did respond five minutes later with a goal by Sergio Santos at 62’, but that ended the scoring on the night with a 5–1 St. Louis City SC win and a move back into 1st place in the Shield race.

One of those Colorado subs, Michael Barrios, got the equalizer in stoppage time to give St. Louis City SC their first draw in franchise history.

A sold-out crowd of 22,423 would not only set an attendance record for a U.S. Open Cup Third Round match,[16][17] but also see St. Louis City SC cruise to a 5–1 win on the backs of Aziel Jackson (3’, 66’), Akil Watts (62’), Löwen (86’) and an Omaha own goal (48’).

Prior to the game, St. Louis City SC loaned out Sam Adeniran to San Antonio FC of USL Championship.

Célio Pompeu would give St. Louis City SC hope, equalizing at 81’, but Portland immediately answered at 82’ to take the lead and the game 2–1.

[21] After traveling to Texas to play half of a game, St. Louis City SC's next match was Tuesday, May 9 at Chicago Fire for their Round 32 matchup in the U.S. Open Cup.

With goals from Löwen (19’), Indiana Vassilev (25’, 75’) and Niko (55’), St. Louis City SC secured a 4–0 win and Bürki's 3rd Clean Sheet of the season.

Hany Mukhtar put Nashville ahead in the 11th minute, but Niko (41’) was able to equalize right before half to give St. Louis City SC hope.

[30] Amidst their toughest stretch of games of the season St. Louis City SC came back home to welcome Real Salt Lake to CityPark on Jun 21.

Looking to make it 3 wins in 3, it took until the 50th minute before Aziel Jackson slid home his first-ever MLS goal to give St. Louis City SC a 1–0 lead.

In the 69th minute Eduard Löwen returned from a quad injury he developed prior to the matchup against Nashville (Jun 17), missing 5 total games.

[37] St. Louis City SC had two players named to the MLS All-Star team: goalie Roman Bürki and defender Tim Parker.

Originally set to kick off at 7:30 pm local time, Jul 23, St. Louis City SC's first visit to Columbus was beset by weather and delayed for nearly four hours.

[41] St. Louis City SC then welcomed Club América to CityPark Jul 27, but due to the quirks of Leagues Cup, they did so as an away team playing in their home stadium.

The 4–0 loss eliminated St. Louis City SC from Leagues Cup and meant they would be sitting idle for more than three weeks while the rest of the tournament played out.

[42] During the summer transfer window, St. Louis City SC added two players: forward Nökkvi Thórisson from Beerschot VA in Belgium [43] and defender Anthony Markanich from the Colorado Rapids.

Sam Adeniran got scoring started in the 22nd minute to put St. Louis City SC up 1–0, but two goals by Alan Pulido sent SKC into half with a 2–1 lead.

[49] Coming off that tight game, St. Louis City SC traveled to the west coast for a Sep 10 matchup against LA Galaxy.

[51] Coming back to CityPark for a midweek matchup Sep 20 against LAFC, St. Louis City SC had a chance to secure a playoff spot with a win.

[52][53] A quick turnaround saw St. Louis City SC back on the road Sep 23 for a Matchday 31 revenge game at Minnesota United FC.

[55][56][57] Furthermore, with LAFC's loss to Real Salt Lake the next day, St. Louis City SC clinched the #1 seed in the Western Conference — the first expansion team ever to accomplish the feat.

They would hold on to win the game 2–0, thwarting St. Louis City SC's chance to tie or overtake LAFC's 57 points in their inaugural 2018 season.