[14] Goalkeeper Paulo Gazzaniga and striker Sam Gallagher were sent out on full-season loans to Rayo Vallecano and Blackburn Rovers, respectively,[15][16] while defender Jason McCarthy and midfielder Dominic Gape moved to Walsall and Wycombe Wanderers, respectively, until January.

[26] On transfer deadline day, the club signed Tunisian goalkeeper Mouez Hassen on loan from Nice until the end of the season,[27] as well as bringing in Italian international striker Manolo Gabbiadini from Napoli in a £14 million deal.

[28] After the window closed, the club also signed Uruguayan centre-back Martín Cáceres, who had been a free agent since leaving Juventus at the end of the previous season.

Southampton began their pre-season preparations against the D.C. United Under-23s on 15 July 2016, winning 2–0 thanks to a first-half goal from James Ward-Prowse and a late penalty by Jay Rodriguez.

[33] Four days later, the side won their third consecutive game by beating FC Twente 2–1, with defender Virgil van Dijk and striker Sam Gallagher getting on the scoresheet.

[41] Laurent Koscielny equalised for the hosts ten minutes later with an overhead kick, and in added time at the end of the game Santi Cazorla scored a controversial penalty to secure the win.

[42] On 25 September, Southampton travelled to the London Stadium to face West Ham United, winning 3–0 to move up to the top half of the league table.

[46] After the break, the home side equalised quickly through Kelechi Iheanacho, but saw a number of chances to win the game prevented by Fraser Forster in the Southampton goal.

[49] Former Saints winger Sadio Mané came close to opening the scoring for the visitors twice in the first half, before Philippe Coutinho, Roberto Firmino and Nathaniel Clyne also missed good chances later on, with the home side's defence playing strongly to keep Liverpool out.

[49] The following week, Southampton beat Everton (managed by former Saints boss Ronald Koeman) by a single early goal to return to tenth in the league table.

[50] Southampton continued to dominate possession and chances on goal throughout the match, with James Ward-Prowse coming closest to doubling his side's lead in the second half.

[53] On 18 December, Southampton travelled to face local rivals Bournemouth, coming from a goal behind to win 3–1 and move up to seventh in the Premier League table.

[55] After dominating much of the rest of the first half, Spurs went ahead shortly after the break through Harry Kane, who missed a penalty a few minutes later when Alli was fouled by Nathan Redmond, who was sent off.

[57] Leighton Baines scored a penalty following a foul by Maya Yoshida on Valencia less than ten minutes later, before Romelu Lukaku made it three before the end of the match.

[59] Morgan was involved again as he brought down Shane Long in the box in the 85th minute, with Dušan Tadić scoring the resulting penalty kick to win the game 3–0.

[64] Dušan Tadić missed a close-range chance on goal before the break, before James Ward-Prowse scored just after half-time to bring the Saints back into the game.

[66] The hosts enjoyed the majority of the pressure after the break, and after a number of close calls Maya Yoshida scored his first league goal of the season to put the Saints in front.

[67] The Baggies came close to equalising at various points throughout the game, with goalkeeper Fraser Forster making a number of saves to deny the hosts and defend the win.

[70] Kamil Grosicki almost scored for the visitors early on with a sixth-minute free kick that hit the post, while Southampton's closest effort came in stoppage time at the end of the game, when Dušan Tadić saw a penalty saved by Eldin Jakupović to keep the Tigers fighting for Premier League safety.

[71] The best chance of the game came for the home side in the second half, when a handball by Jack Stephens resulted in a penalty; however, James Milner's spot kick was saved by Fraser Forster and the scores remained level.

[73] With a markedly changed lineup (including the debut of centre-back Martín Cáceres), the Saints started the game slowly, but opened the scoring through Jay Rodriguez shortly before half-time.

[78] In the replay at St Mary's Stadium, Southampton beat Norwich City by a single late goal to advance to the fourth round of the FA Cup.

[82] After the break, young midfielder Jake Hesketh scored his first goal for the club (in his first senior appearance since December 2014) to double Southampton's lead, which they held until the end to ensure their place in the fourth round of the tournament.

[84] The only goal of the game was scored by Moroccan winger Sofiane Boufal's long-range strike into the top corner, on his first start for the home side since his move in the summer.

[85] Jordy Clasie opened the scoring within the first 15 minutes of the game with his first goal for the club, striking from the edge of the penalty area after Sofiane Boufal's initial effort was blocked.

[85] The home side increased the pressure in search of an equaliser, but the Saints struck again through Ryan Bertrand shortly before half time to double their lead going into the break.

[86] Liverpool enjoyed the majority of possession early in the match, but Nathan Redmond opened the scoring for the hosts within 20 minutes with his first goal in the competition, after being set up by Jay Rodriguez.

[87] Liverpool dominated possession throughout the majority of the game, but the Saints enjoyed more clear-cut chances to score in the first half, with Dušan Tadić and Steven Davis coming closest to breaking the deadlock.

[90] The game did not feature many goalscoring opportunities for either side in the first half, which Hapoel largely dominated, although James Ward-Prowse had a number of chances on goal after the break.

[92] After Inter captain Mauro Icardi opened the scoring in the 33rd minute, the Saints were awarded a controversial penalty for a handball by Ivan Perišić just before half time, while Antonio Candreva was booked for an off-the-ball incident involving Sam McQueen.