The club ended the season hosting local rivals Portsmouth in the annual Hampshire Benevolent Cup charity match, which they won 3–1 thanks to two goals from Arthur Dominy and one from Bill Rawlings.

Most significant of the departures was inside-left James Moore, who had played every game the previous campaign; he returned to his native county of Yorkshire due to "family reasons", joining Second Division club Leeds United.

[1] He was replaced in the side by Henry Johnson, who had joined from Darlaston just before the end of the last season,[2] and new addition Len Andrews, who was signed from Reading in August (he had previously played over 100 games for the Saints before World War I).

[3] Goalkeeper Arthur Wood, who had lost his place the previous year to new signing Tommy Allen, also left the club in May 1921 to join Second Division side Clapton Orient, where he remained for the rest of his career.

[4] Three more players left in the summer, all of whom had spent only one season at the club – centre-forward George Reader retired from the professional game and joined Harland and Wolff on a part-time basis,[5] outside-right Frank Wright returned to his previous position at Hamstead Colliery,[6] and inside-right George Williams joined fellow Third Division South side Exeter City, where he played for a season before being forced to part-retire due to a leg injury.

McIntyre's contributions were outside-left Fred Foxall and outside-right Joe Barratt, both of whom had played the majority of games up to that point, while their replacements were inside-left Jack Elkes and half-back George Getgood.

[12] Foxall had originally attempted to join top-flight side Aston Villa in May, but his transfer was reversed by the Football Association as Southampton had not given permission for the sale (he was also ordered to donate his signing-on fee to the National War Fund).

[18] However, the side's fortunes quickly changed when they embarked on a club record 19-game unbeaten league run, beginning on 5 September with a 2–1 win over Luton at The Dell and not ending until the following January, over four months later.

[18] New signings Jack Elkes and George Getgood debuted against Southend United in the next game, with the former scoring two goals in the convincing 5–2 win; however, he broke his collar bone in the next match, and remained injured for the remainder of the campaign.

[22] In their final game of the campaign, Southampton thrashed Newport County 5–0 in the return fixture at The Dell, with goals coming from Arthur Dominy (two), Alec Campbell, Rawlings and Henry Johnson.

Despite their lower league status, the Saints picked up a "convincing" 3–1 win over the second-tier club, with goals from Henry Johnson, Bill Rawlings and Arthur Dominy.

[27] Two days after the conclusion of the Third Division South campaign, Southampton and Portsmouth faced off again (for the fifth time that season) in the annual Hampshire Benevolent Cup fixture.

[18] Three players appeared in all 45 league and FA Cup matches: goalkeeper Tommy Allen, right-half Bert Shelley and left-back Fred Titmuss.