Remarkably, the Saints have won their last two games at the Theatre of Dreams under former manager Ronald Koeman and haven’t lost at Old Trafford since January 2013.
United appointed Mourinho as Louis van Gaal’s successor in May after a disappointing fifth-place finish in the Premier League last season.
Enhanced odds: Get 4/1 on Manchester United to beat Southampton
The new manager has already signed Villarreal defender Eric Bailly, Swedish legend Zlatan Ibrahimovic, Borussia Dortmund midfielder Henrikh Mkhitaryan and France international Paul Pogba in the summer transfer window.
Mourinho’s new-look side were 3-1 winners against Southampton’s south coast rivals Bournemouth at Vitality Stadium in their Premier League opener last weekend.
Former Liverpool and United striker Owen is confident the Red Devils will ease to victory without conceding a goal at Old Trafford on Friday night.
“Saints have won their last two league games at Old Trafford by the only goal of the game but have never won three in a row there in their entire league history,” Owen told Bet Victor.
“I expect to see Jose Mourinho’s side buck that trend and go top-of-the-table.”
United are at the top of the Premier League table after last weekend’s 3-1 victory over Bournemouth ahead of Liverpool and Chelsea.
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