Rickie Lambert and Adam Lallana were both on the scoresheet in the first half at St Mary's Stadium as Mauricio Pochettino's men made it four top-flight wins in a row at home.
The home side went ahead early on, with Morgan Schneiderlin taking advantage of poor defending in the Hull ranks to head home Lambert's knock-down.
Lallana was instrumental in the second, as he looked to get onto the end of a Lambert pass, only for the onrushing Steve Harper to take him down. Lambert then emphatically converted the penalty to maintain his 100 per cent record from the spot for Southampton from 33 attempts.
Southampton's third came courtesy of Lallana, after 36 minutes. The 25-year-old jinked his way into the area before calmly slotting the ball past Harper from a tight angle.
Yannick Sagbo pulled a goal back for Hull early in the second half following an error from Victor Wanyama. However, any hopes of a comeback had all but disappeared by the time Steven Davis hit a low drive past Harper in the closing stages.
Hull were unchanged from their last Premier League outing, which saw them beat Sunderland 1-0, although there was no place on the bench for Robbie Brady, who continues to struggle with a hernia problem.
Southampton were also unchanged, but recalled Pablo Daniel Osvaldo to the squad with the Italy international having recovered from a nerve problem.
Lambert, Lallana and Jay Rodriguez started for Pochettino, following their England call-ups, while 18-year-old Sam Gallagher made his first appearance in a league squad for Southampton.
Southampton edged a slow-paced opening 15 minutes and were rewarded when Schneiderlin recorded his first goal of the season from close range after 16 minutes.
Pochettino's side doubled their lead 14 minutes later, with Lambert converting a penalty after Lallana was brought down in the area by Harper, who was booked.
The hosts continued to demonstrate their clinical streak, edging 3-0 ahead six minutes later courtesy of Lallana's third Premier League goal of the season.
Southampton had kept clean sheets in their previous four home Premier League games, but Hull got on the scoresheet nine minutes after the break, Sagbo coolly finishing after George Boyd pounced on a dithering Wanyama, who was withdrawn soon after.
Tom Huddlestone was next to threaten with a long-range effort before Lallana forced a save from Harper after good link-up play with Lambert in the Hull box.
Substitute Davis capped off a comprehensive win for the home side two minutes from time, swivelling well and finishing Nathaniel Clyne's cross.
