Saints had seen their cushion at the summit disappear following successive defeats to Bristol City and Brighton as West Ham moved level on points with them.
But goals from Guly Do Prado, David Connolly and Morgan Schneiderlin got Nigel Adkins' side back on track as they remained ahead of the Hammers on goal difference.
It was a first away victory in the league for Saints in more two months.
For Forest, who had captain Luke Chambers sent off early in the second half, it signalled a fifth straight home league loss and left them languishing in the relegation places.
Marlon Harewood started a match for Forest for the first time in more than eight years as Reds boss Steve Cotterill made two changes.
Harewood made his City Ground return as a second-half substitute in the FA Cup against Leicester last weekend after signing a deal until the end of the season following a spell in Chinese football.
The striker's last start for the club was a goalscoring one in a 2-2 draw at Wigan in the old Division One on 22 November 2003.
He came into the team along with on-loan Manchester City full-back Greg Cunningham, fit again after a hamstring injury, as Andy Reid and Kieron Freeman were replaced.
Southampton made three changes with goalkeeper Kelvin Davis and strikers Do Prado and Connolly recalled after being rested against Coventry in the cup.
Forest goalkeeper Lee Camp was called into early action when he had to tip a long-range effort from Dean Hammond round a post.
Harewood was denied what looked like a certain goal midway through the first half when Jos Hooiveld made a superb last-ditch block inside the six-yard box.
Saints took the lead shortly afterwards following an attack down the right. Camp made a block following Connolly's cross, but Do Prado was on hand to tap in his 11th goal of the season after 27 minutes.
Joel Lynch should have equalised just after the half-hour mark, but the defender headed over the crossbar when Lewis McGugan picked him out at the far post from a corner.
Forest were reduced to 10 men in the 50th minute when referee Eddie Ilderton decided that Chambers had led with his arm in an aerial challenge with Connolly.
Gaps began to appear in the home defence as a result and Saints picked them off in the 65th minute when Connolly was teed up by Schneiderlin. The Irishman finished from close range for his sixth goal of the season.
Schneiderlin scored himself with 11 minutes remaining, finding the bottom left-hand corner with a well-struck right-foot shot from long distance.
Had it not been for Camp it would have been more. The Northern Ireland international tipped efforts wide from substitute Lee Holmes and Daniel Fox and pushed another shot from Hammond over the bar as Southampton continued to dominate.