Kevin De Bruyne followed in after Alex McCarthy parried a Phil Foden low-driven shot, smashing the ball in off the crossbar and giving Manchester City the lead after 15 minutes and getting his first of the night.
The lead did not last long, however, as James Ward-Prowse converted his seventh goal of this Premier League season from the penalty spot.
Riyad Mahrez scored two classic Mahrez-esque goals. The first came after the winger cut in from the right and bent a shot into the far post, with the second capitalising on a Southampton mistake.
Che Adams gave The Saints hope with a smash-and-grab shot, but it was sandwiched between an İlkay Gündoğan poachers goal and De Bruyne's technical second, ending the chance of a Southampton comeback once and for all.
Back to where it all began
A 1-0 win at St Mary's Stadium all the way back in December saw the start of a record-breaking winning run of 21 consecutive games, which was eventually ended at the weekend in the Manchester Derby.
In that time, City tallied up a total of 54 goals scored and kept 13 clean sheets, whilst only shipping 10 goals.
The reverse fixture in December saw a slim 1-0 win for City, a Raheem Sterling strike being the only difference between the sides.
Although Southampton had a rampant start to the season, seeing the side sat at the top of the table in late November, Ralph Hassenhutl's Saints are all the way down in 14th position, after suffering from goal droughts from Danny Ings and Adams and a torrid set of injuries.
Veterans return
Fernandinho starting and Sergio Agüero coming off the bench for some crucial minutes will have put smiles on the faces of all Citizens watching, with the two club legends playing for City once again.
Agüero, who is nearing the end of his contract at City, has had a very difficult season so far. The Argentine has only played 220 league minutes, registering no goal or assist. It has been a long 14-month long drought since his last league goal.
The Brazilian midfielder, who has been at the club since 2013, controlled the midfield all night - an impressive match for the 35-year-old, who has only completed 90 minutes on seven occasions in the 2020/21 Premier League season.
Player of the Month
What a month it has been for Mahrez. Following multiple amazing performances in February, which won the Algerian Manchester City’s Player of the Month award, he continued to impress with two wonderfully-worked goals against The Saints.
Both goals were reminiscent of the Leicester Mahrez, evading the defenders, leaving them in his dust, and giving the keeper absolutely no hope with his finish.
The winger beat Bernardo Silva and Rodri to the award after accruing 79% of the votes from City fans.
“The last games were outstanding. He played really well. He has a special quality,” Pep Guardiola told Manchester City website.
“He is a guy who dances on the pitch. He doesn’t lose balls on the pitch. He makes the extra pass. He attracts opponents on the pitch and after he makes a pass in behind."
The Belgian is back
For all those worrying following a couple of poor displays from De Bruyne, they were comforted by a brilliant brace from the Belgian midfielder.
The world-class midfielder has been struggling since his return to the side after six weeks on the sideline, with many fans calling for Bernardo to replace him for a game or two.
However, Guardiola kept his faith in the star and of course, made the right call as he led City to victory over Southampton to keep the gap between them and United at 14 points.
Outscoring the opponent
Luckily for the City defenders on Wednesday night, the attackers in blue had their shooting boots strapped on, putting away five well-taken goals to shake off a resilient Southampton side.
A relatively poor defensive display from Ruben Dias and Laporte saw Ward-Prowse tuck away a penalty and Adams smash home after a lucky bounce landed at the feet of the Englishman.
This result, along with the 2-0 defeat to Manchester United on Sunday afternoon, means that City have shipped two goals in successive games for the first time since December 2018 when they lost to Crystal Palace (mainly thanks to an Andros Townsend wonder strike) and Leicester City.