After leading the club for the second half of the 1999–2000 season, Glenn Hoddle remained Southampton manager for most of the 2000–01 campaign, although he left in March 2001 and was replaced by Stuart Gray, who saw out the year.

The Saints struggled in the league early on, spending a few weeks in the relegation zone; by the new year, however, they had made it up to the mid-table region, with a string of five wins ahead of Hoddle's departure taking them as high as 8th.

In the fifth round they faced another second-flight side, Tranmere Rovers, who beat the Saints 4–3 in a replay (after a goalless draw at The Dell) by overcoming a 0–3 half-time deficit with four second-half goals.

[7] August also saw the retirement of three Saints players from professional football – left-back John Beresford was forced to leave due to a cruciate ligament injury suffered in the opening game of the 1998–99 season, since which he had only managed to make three substitute appearances for the club;[8] attacking midfielder David Hughes was forced to step down after failing to recover from a knee injury suffered in a pre-season match ahead of the 1999–2000 season;[9] and defensive midfielder David Howells left after nearly 18 months without an appearance, due to the recurrence of an old knee injury suffered prior to joining Southampton.

[10] In September, Argentine winger Adrian Caceres joined from Australian side Perth for £25,000,[11] while centre-back Richard Dryden moved to Northampton Town for two months in the first of two loan spells during the season.

[12] During October, Portuguese winger Dani Rodrigues spent a few weeks on loan at Bristol City in the Second Division, before breaking his ankle and being forced to return to Southampton for rehabilitation.

[15] Around the same time, new signing Patrice Tano was released due to issues with his passport and work permit, which forced him to move back to France.

[18] After Christmas, the club signed Romanian right-back Dan Petrescu from Premier League strugglers Bradford City, paying a "nominal fee" for the defender.

[19] Petrescu had originally planned to sign for the Saints from Chelsea at the beginning of the season after falling out with manager Gianluca Vialli,[20] however an £800,000 deal fell through after the defender could not agree to personal terms.

[25] Home debutant Keith Jones opened the scoring in the 21st minute with a "spectacular volley", and it took the visitors until "virtually the last kick of the game" to equalise, with substitute Garry Monk tapping in from close range.

[34] The run culminated in the club's heaviest defeat of the season, as they lost 0–5 to reigning champions Manchester United at Old Trafford, with Andy Cole scoring twice and Teddy Sheringham completing a hat-trick.

[33] After winning both of their games with clean sheets between Christmas and new year (2–0 against Tottenham Hotspur and 1–0 against Derby County), Southampton sat 12th in the Premier League table.

[38] Two goalless draws followed, before a 1–0 win at home to Leicester City in which Dan Petrescu scored the only goal of the game in his full debut since joining a few weeks earlier.

[38] The victory marked the start of Southampton's best run of form all season, as they won five games in a row without conceding a single goal – after Leicester, the Saints beat four teams in the bottom six of the table: 2–0 against Bradford City (Pahars and Beattie scored), 1–0 away at both Middlesbrough (Mark Draper with his only goal of the season) and Manchester City (Petrescu scoring again), and 1–0 at home to Everton (thanks to a Jo Tessem strike).

[39] In late-March, shortly after George Graham was sacked as Tottenham Hotspur manager,[40] Hoddle left Southampton after holding talks to take over the vacated role at his former club.

[41] He was confirmed as the new Tottenham boss on 30 March, claiming that "It wasn't an easy decision to leave Southampton because I have put in a lot of hard work".

[38] Another defeat without scoring followed five days later, as 4th-place Leeds United beat the Saints 2–0 at Elland Road with goals from Harry Kewell and Robbie Keane either side of the break.

Despite looking like it would finish a draw, the game was decided in the penultimate minute when Matt Le Tissier – making only his 8th appearance in the league campaign – scored a left-foot volley to give the hosts all three points.

The top-flight hosts came closest to opening the scoring in the first half, with Jo Tessem, Kevin Davies and James Beattie all failing to convert chances at various points.

[50] The tide turned again late in the game, when a Booth handball led to a penalty for the Saints, which Dodd again converted for 2–1, before Beattie completed a win with a header in the last minute.

[50] Another offside decision prevented a goal for the Saints around 20 minutes later, when Hassan Kachloul scored from a Marians Pahars pass, and the sides ultimately went into half-time goalless.

[50] Southampton continued to dominate after the break, but were unable to make any of their efforts count and it ended 0–0, forcing a replay at Prenton Park three days later.

The Saints beat the Stags 5–1 on aggregate over two legs, with Jo Tessem and Matt Le Tissier securing a 2–0 win at The Dell, before Uwe Rösler and Trond Egil Soltvedt (two) added a 3–1 victory at Field Mill.

[25] The first two took place in March against French side Le Havre, reportedly as a mechanism for manager Glenn Hoddle to "look at seniors returning to fitness and youngsters hoping to press their claims" during the final stages of the season.

[54] Southampton lost the return fixture at The Dell by the same margin, with goals either side of the break from Thomas Deniaud and Karim Kerkar giving Le Havre the 2–0 win.

[25] Featuring a rotating cast of players on either side, the game ended in a 3–1 win to Taylor's side, with goals scored by former Saints players Steve Davis and Nicky Banger in the first half, followed by guest Dean Gaffney just before the end, who scored against goalkeeper Matt Le Tissier after a penalty by chairman Rupert Lowe had hit the crossbar.