But City's fightback at least made sure they did not lose any more ground on Liverpool, who also produced a late comeback to win 2-1 at Aston Villa, with six points separating the top two ahead of their showdown at Anfield next weekend.
Mane had been booked for diving earlier in the game, which Liverpool won 2-1.
"Every three points is vital".
Leroy Sane's absence through injury is evident and the German is exactly the player that City need back if they're going to challenge Liverpool for the title.
James Ward-Prowse pounced for the opener after 13 minutes following a mistake by Ederson. Walker grabbed the victor with four minutes to play after Alex McCarthy palmed an Angelino cross in his direction.
"We were concentrating on our game", said the City right-back, whose appearances in recent weeks have been restricted by illness.
Guardiola's agitation was obvious as he turned into the world's best paid ball boy for much of the second half, trying to keep the momentum high as City pressed forward, and the Catalan clashed a few times with Southampton's coaches as he tried to retrieve the ball.
"If it's one time, two times, "we were lucky, we were lucky", but it happened in the last two seasons many, many times".
Saints' much-maligned defence, the worst within the Premier League with 25 targets conceded and with no clear sheet on this fixture with Metropolis for 15 years, carried out with bravery and self-discipline in blocking each Metropolis first half assault.
"It's tough when teams put 11 players behind the ball".
"Football players have pride, they did not want to live again in that position", Guardiola said of Southampton's response to last week's horror show.
Manager Ralph Hasenhuttl said: "It's important for us to see we can defend in that way against such a team, but we know Everton (next week) is a completely different game".
"It's a great feeling that I can contribute but more importantly it was about the three points".