Made captain for his final appearance, Lampard left the action in the 77th minute to a huge ovation from all sides of the ground before the prolific Sergio Aguero grabbed the second from close range three minutes from time.
It was the Argentinian’s 26th Premier League goal of the season and underlined his status as golden boot winner.
But the main headlines were taken by Lampard, who signed off with his 259th goal in his 882nd club appearance in English club football.
City fielded a midfield trio of players who may not be at the Etihad Stadium next season, with Yaya Toure and James Milner also starting. They too were also substituted to warm appreciation during the second half.
Aguero was twice denied in the first half by Southampton’s veteran goalkeeper Kelvin Davis, who caught the eye on his 300th and possibly final appearance for the club.
The end-of-season feel was evident among the visitors’ large and vociferous following, many of whom wore orange in tribute to their Dutch manager Ronald Koeman.
Saints did have Europa League concerns and showed early bite with Filip Djuricic skipping past Martin Demichelis only to be hacked down. Referee Chris Foy – another bidding farewell to the Premier League scene – showed the yellow card.
Joe Hart then foiled Shane Long and Toure tested Davis from the edge of the area. The keeper could only parry but was alert enough to smother Aguero’s effort on the rebound.
City went ahead when Milner pulled the ball back for Lampard who, in trademark fashion, timed his run to perfection and smashed into the roof of the net.
City almost immediately had a second after Silva again fed Aguero but Davis once more thwarted the Argentinian.
Southampton were starved of possession but Graziano Pelle fired a chance wide.
and the contest did seem to be winding down to a conclusion when Aguero popped up for his goal.
Eliaquim Mangala headed back across goal after a Jesus Navas shot was blocked and Aguero pounced at the far post with a close-range header.
Hart, Zabaleta, Demichelis, Mangala, Kolarov, Toure (Bony 66),Fernandinho, Milner (Kompany 79), Lampard (Jesus Navas 77), Silva, Aguero.
Kelvin Davis, Clyne, Fonte, Alderweireld, Bertrand, Wanyama, Steven Davis (Elia 76), Long, Djuricic (Ward-Prowse 59), Mane, Pelle.
Chris Foy (Merseyside).