United made it difficult for the Saints to settle into the game, firing an early warning shot through Robin van Persie and holding the ball in the midfield.
The hosts soon steadied the ship and started playing some good football in the final third. They took a surprise lead when Jason Puncheon's cross found Rickie Lambert at the back post, who headed home for 1-0.
It was Southampton's first Premier League goal at St. Mary's since 2005, but it wasn't long before United levelled the match.
Antonio Valencia whipped in an invited ball to Van Persie, and the Dutch international took the ball on his chest and hit the back of the net with a half-volley.
Lambert almost restored the hosts' lead immediately, but his left-footed drive from outside the box drifted narrowly wide of the post.
The home side continued to threaten until the half-time whistle, with Lambert and Adam Lallana proving a handful for the home defence.