The former Chelsea man opened the scoring for the deposed Premier League champions before Sergio Aguero made sure of victory with two minutes left on the clock
Lampard joined City in August, despite having previously agreed a move to sister club New York City to seemingly bring his Premier League days to a halt, but the 36-year-old has continued to be an asset and he brought his era to a fitting close by netting on Sunday.
Yaya Toure and James Milner, both of whom have been strongly linked with summer moves, also lined up for potentially their final games for City, though ultimately it was Lampard – wearing the captain's armband – who made the biggest difference.
Sergio Aguero wasted several opportunities but netted his 26th of the season late on, capping a campaign that sees him win the Premier League golden boot.
Southampton improved after the break, but Manuel Pellegrini's men held firm to give Lampard a happy send-off, while the visitors' bid for a Europa League place now rests on Arsenal beating Aston Villa in the FA Cup final.
IN PICTURES The final day of the 2014-15 Premier League season
Despite what has ultimately proved to be a disappointing season for City after the surrendering of their Premier League crown, a fine atmosphere greeted the deposed champions for their final contest of the season.
The chances eventually began to flow, and in the 24th minute Kelvin Davis was forced to spare his own blushes, denying Aguero from point-blank range after initially dropping a tame effort at the Argentina striker's feet.
But the breakthrough finally arrived in the 31st minute, Lampard marking an emotional day in fitting style when he met Milner's low cross with an emphatic first-time effort following a trademark late run into the area.
Aguero should have added to the score shortly after, though Davis did well to thwart the striker when one-on-one.
The goalkeeper was tested again in the 37th minute, palming wide after a ricochet off Toby Alderweireld looked set to find the top-right corner.
The contest opened up early in the second half with Southampton pouring forward and causing Eliaquim Mangala and company at the back plenty of problems.
But the visitors were continuously caught offside, with Graziano Pelle twice guilty of not holding his run when fine opportunities looked set to present themselves.
Southampton finally tested Joe Hart with a legitimate shot on goal but Shane Long's feeble first-time effort from 25 yards rolled along the ground and gave the England international an easy task.
The biggest cheers of the half were reserved for Lampard, Toure and Milner, as the midfield trio milked thunderous applauses in the final 25 minutes as they were substituted.
And the celebratory mood was rounded off with the visitors pushing on and leaving themselves open at the back, allowing City to capitalise through Aguero, who added a second with a close-range header two minutes from time.