The Championship side beat the Gunners 2-1 in the quarter-finals at St Mary’s on Saturday.
City thrashed Liverpool 4-0 on Saturday to reach the semi-finals of the competition for an eighth successive season.
Pep Guardiola’s side are bidding to make the final for a fourth consecutive year, having lost to Manchester United in 2024 and Crystal Palace in 2025 following their last win in 2023.
Southampton are dreaming of emulating their shock 1976 FA Cup final victory against Manchester United.
Relegated from the Premier League last season, Southampton are also hoping to win promotion via the Championship play-offs.
Leeds, who lifted the FA Cup in 1972, will meet Chelsea in the other Wembley semi-final after a dramatic conclusion to their quarter-final clash with West Ham on Sunday.
Daniel Farke’s team led 2-0 at the London Stadium, but West Ham scored twice in stoppage time to force extra time.
Leeds eventually won 4-2 on penalties to earn a place in the last four for the first time since 1987, when they were beaten by Coventry.
Chelsea, 7-0 winners against third-tier Port Vale on Saturday, famously beat Leeds in a brutal 1970 FA Cup final that went to a replay.
Draw for the English FA Cup semi-finals made on Sunday:
Chelsea vs Leeds
Manchester City vs Southampton
Ties to be played at Wembley on the weekend of April 25 and 26.
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