Dean Hammond, Adam Lallana and David Connolly were on target as Nigel Adkins' newly-promoted side began the season in style.
Leeds pulled one back in stoppage time when Max Gradel scored from the penalty spot but game was well and truly up by then.
These teams met in the Premier League just seven years ago but both have since plumbed the depths of League One.
And on this early evidence, it is the south-coast side who look better equipped to challenge for promotion back to the top flight this term.
Leeds did squander a great chance to go ahead in the eighth minute when Jonathan Howson shot straight at Saints goalkeeper Kelvin Davis, who was able to make a fine reaction save.
But less than two minutes later the hosts took the lead - and they never looked back.
Hammond collected the ball midway inside the Leeds half, strode forward unchallenged and fizzed a precise shot past the outstretched arm of Andy Lonergan and inside the post.
Slick Saints doubled their advantage in the 24th minute when Rickie Lambert played in England Under-21 international Lallana, who turned inside lone defender Andy O'Brien before tucking the ball past Lonergan.
Shell-shocked Leeds were almost three down moments later when the ball fell to Lallana in the area again -
but this time Lonergan was able to beat out his effort.
Lambert, a prolific goalscorer in the lower divisions, is desperate to prove he can cut it in the Championship and nearly opened his account with a free-kick which hit the side-netting just before the interval.
Leeds came out after half-time knowing the next goal would be crucial - and unfortunately for them it went to Southampton.
Veteran frontman Connolly played a superb one-two with Lallana, flicking the ball into the midfielder's path and collecting the return before sliding it past Lonergan.
Leeds should have grabbed a lifeline on the hour mark when Billy Paynter found himself through on goal but Davis managed to get a hand on the striker's shot and the opportunity was lost.
Gradel then had a tantrum in the area when his penalty claim was waved away after he was challenged by Jack Cork.
It could have got even worse for the visitors but Aaron Martin headed a good chance into the ground and over the crossbar and Richard Chaplow crashed a shot against the post.
And Leeds grabbed their consolation in injury time when Martin handled and Gradel took his frustration out on the ball, crashing the penalty past Davis.