| 1 | Sun 22 Aug 2021 | 21-1 v Manchester UnitedSouthampton 1-1 Manchester United | Premier League |
| 2 | Wed 25 Aug 2021 | 28-0 v Newport CountyNewport County 0-8 Southampton | Carabao Cup Second Round |
| 3 | Sat 28 Aug 2021 | 2 2-2 v Newcastle UnitedNewcastle United 2-2 Southampton | Premier League |
| 4 | Sat 18 Sep 2021 | 2 0-0 v Manchester CityManchester City 0-0 Southampton | Premier League |
| 5 | Sun 26 Sep 2021 | 20-1 v Wolverhampton WanderersSouthampton 0-1 Wolverhampton Wanderers | Premier League |
| 6 | Sat 2 Oct 2021 | 21-3 v ChelseaChelsea 3-1 Southampton | Premier League |
| 7 | Tue 26 Oct 2021 | 21-1 v ChelseaChelsea 1-1 Southampton | Carabao Cup Round of 16 |
| 8 | Sat 30 Oct 2021 | 21-0 v WatfordWatford 0-1 Southampton | Premier League |
| 9 | Fri 5 Nov 2021 | 21-0 v Aston VillaSouthampton 1-0 Aston Villa | Premier League |
| 10 | Sat 20 Nov 2021 | 2 1-2 v Norwich CityNorwich City 2-1 Southampton | Premier League |
| 11 | Sat 27 Nov 2021 | 20-4 v LiverpoolLiverpool 4-0 Southampton | Premier League |
| 12 | Wed 1 Dec 2021 | 22-2 v Leicester CitySouthampton 2-2 Leicester City | Premier League |
| 13 | Sat 4 Dec 2021 | 21-1 v Brighton & Hove AlbionSouthampton 1-1 Brighton & Hove Albion | Premier League |
| 14 | Sat 11 Dec 2021 | 20-3 v ArsenalArsenal 3-0 Southampton | Premier League |
| 15 | Wed 15 Dec 2021 | 22-2 v Crystal PalaceCrystal Palace 2-2 Southampton | Premier League |
| 16 | Sun 26 Dec 2021 | 2 3-2 v West Ham UnitedWest Ham United 2-3 Southampton | Premier League |
| 17 | Tue 28 Dec 2021 | 2 1-1 v Tottenham HotspurSouthampton 1-1 Tottenham Hotspur | Premier League |
| 18 | Sat 22 Jan 2022 | 21-1 v Manchester CitySouthampton 1-1 Manchester City | Premier League |
| 19 | Sat 5 Feb 2022 | 2 2-1 v Coventry CitySouthampton 2-1 Coventry City | Emirates FA Cup Fourth Round |
| 20 | Wed 9 Feb 2022 | 23-2 v Tottenham HotspurTottenham Hotspur 2-3 Southampton | Premier League |
| 21 | Sat 12 Feb 2022 | 21-1 v Manchester UnitedManchester United 1-1 Southampton | Premier League |
| 22 | Sat 19 Feb 2022 | 22-0 v EvertonSouthampton 2-0 Everton | Premier League |
| 23 | Fri 25 Feb 2022 | 22-0 v Norwich CitySouthampton 2-0 Norwich City | Premier League |
| 24 | Wed 2 Mar 2022 | 23-1 v West Ham UnitedSouthampton 3-1 West Ham United | Emirates FA Cup Fifth Round |
| 25 | Sat 5 Mar 2022 | 20-4 v Aston VillaAston Villa 4-0 Southampton | Premier League |
| 26 | Thu 10 Mar 2022 | 21-2 v Newcastle UnitedSouthampton 1-2 Newcastle United | Premier League |
| 27 | Sun 13 Mar 2022 | 21-2 v WatfordSouthampton 1-2 Watford | Premier League |
| 28 | Sun 20 Mar 2022 | 21-4 v Manchester CitySouthampton 1-4 Manchester City | Emirates FA Cup Sixth Round |
| 29 | Sat 2 Apr 2022 | 21-1 v Leeds UnitedLeeds United 1-1 Southampton | Premier League |
| 30 | Sat 9 Apr 2022 | 20-6 v ChelseaSouthampton 0-6 Chelsea | Premier League |
| 31 | Sat 16 Apr 2022 | 21-0 v ArsenalSouthampton 1-0 Arsenal | Premier League |
| 32 | Thu 21 Apr 2022 | 20-2 v BurnleyBurnley 2-0 Southampton | Premier League |
| 33 | Sun 24 Apr 2022 | 22-2 v Brighton & Hove AlbionBrighton & Hove Albion 2-2 Southampton | Premier League |
| 34 | Sat 30 Apr 2022 | 21-2 v Crystal PalaceSouthampton 1-2 Crystal Palace | Premier League |
| 35 | Sat 7 May 2022 | 20-3 v BrentfordBrentford 3-0 Southampton | Premier League |
| 36 | Tue 17 May 2022 | 21-2 v LiverpoolSouthampton 1-2 Liverpool | Premier League |
| 37 | Sun 22 May 2022 | 21-4 v Leicester CityLeicester City 4-1 Southampton | Premier League |
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