Hull City moved back into the Championship play-off places and put a dent in Southampton's automatic promotion hopes by winning at St Mary's.
The Saints had won nine consecutive home league games prior to this one, but first-half goals from on-loan pair Anass Zaroury and Fabio Carvalho earned the Tigers a valuable win.
Substitute Joe Aribo pulled a goal back for Saints late in the game but it was not enough to prevent a fourth consecutive away victory for Liam Rosenior's side, a run that has helped them back in the top six.
Southampton, who had not lost at home to Hull since 1951, have lost two of their past three games following their club-record 25-match unbeaten run.