The two other fancied sides, Tottenham Hotspur and Manchester United were thrown together in a glamorous tie.
Both ties will be at Wembley Stadium, which has been Spurs' home ground this season while White Hart Lane is being rebuilt.
The matches will take place on 21 and 22 April.
Bookmaker William Hill made Chelsea 13/8 favourites with Tottenham 2/1, United 9/2 and Southampton 9/1.
It was a good day for Chelsea manager Antonio Conte, who is widely expected to leave at the end of the season, only 12 months after winning the Premier League.
Losing to Barcelona in the Champions League in midweek meant the FA Cup was the last trophy his team could win to salvage a disappointing season.
They were taken to extra time in the quarter-final at Leicester City, but substitute Pedro scored to earn a 2-1 win.
Now they will be up against a former Stamford Bridge hero in Mark Hughes, whose first match as manager of Southampton brought a 2-0 win at Wigan Athletic in Sunday's other quarter-final.
Hughes played for them from 1995-98, winning the cup in 1997.
This season Chelsea beat Southampton 1-0 at Stamford Bridge in December. The teams will meet on successive weekends as the return game is at Southampton on 14 April.
"When you arrive at this point, every game is difficult," Conte said. "Southampton have just changed coach but now it is important to be happy and to go for another game at Wembley. If you can win a trophy it is important for a team like Chelsea."
Spurs and Manchester United have shared the points in their two league meetings this season.
United won 1-0 at Old Trafford in October but were beaten 2-0 at Wembley in January, conceding the opening goal to Christian Eriksen after 11 seconds.
(Reporting by Steve Tongue, editing by Pritha Sarkar)
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