Southampton were punished for several missed chances as Inter Milan eased the pressure on manager Frank de Boer by snatching victory in their Europa League group game at the San Siro.
The Premier League side outplayed their hosts in the first half, but James Ward-Prowse fired over and Cuco Martina shot wide.
Substitute Charlie Austin powered a low strike just wide after the break as Saints lacked the cutting edge to score the goal their play deserved.
Inter, who had lost their past three games, rarely threatened before Antonio Candreva lashed a shot into the top corner.
Marcelo Brozovic’s late dismissal for two bookings gave Southampton renewed hope, with both Virgil van Dijk and Austin denied from point-blank range.
But the visitors could not find an equaliser as they slipped to their first defeat in the Europa League this season.