Yoan Gouffran's goal gave the Magpies the advantage but Mauricio Pochettino's halftime changes improved the visiting side, which has now not won in its last five games.
Jay Rodriguez's seventh goal in all competitions this season canceled out a first-half opener from Yoan Gouffran, the Frenchman's fourth strike in his last four home matches.
Both sides had chances to win it in what proved to be a very open second half, with Loic Remy guilty of spurning a glorious one-on-one opportunity late on.
Ultimately, however, Southampton saw its winless league run extended to five games, while the hosts were denied a sixth victory in their last seven top-flight fixtures.
Newcastle manager Alan Pardew, facing his former club, was without the suspended Yohan Cabaye, who picked up his fifth booking of the campaign before scoring the winner against Manchester United last time out, with Shola Ameobi coming in.
Mauricio Pochettino selected defender Jos Hooiveld in place of Jose Fonte, while midfielder Adam Lallana was surprisingly dropped to the bench alongside groin injury victim Morgan Schneiderlin.
Newcastle made most of the early running and Mathieu Debuchy flashed a volley from the edge of the box narrowly wide after five minutes.
The home side should have taken the lead six minutes later when Gouffran beat Paulo Gazzaniga to the ball, cut it back for Remy and the striker's close-range effort was cleared off the line by Calum Chambers.
The pressure finally told in the 27th minute as Southampton failed to defend a free kick from the halfway line and Gouffran pounced on Mike Williamson's flick-on to side step the goalkeeper and roll home his fifth league goal of the season from six yards out.
A rare Southampton attack late in the half forced a corner that Tim Krul punched clear as Newcastle went into the break with the lead intact.
Pochettino made two changes at the interval, with Lallana replacing Pablo Daniel Osvaldo and Schneiderlin coming on for James Ward-Prowse.
The visiting side looked more threatening initially, Rodriguez scuffing a volley wide after latching on to Rickie Lambert's lofted pass.
Remy saw a low long-range strike well kept out at the other end, with strike partner Ameobi heading well wide from a corner in the 57th minute.
Steven Davis hit the post with a well-struck long-range volley just after the hour mark but Newcastle failed to heed the warning.
Rodriguez broke from just inside the home team's half and played a one-two with Davis before rolling the equalizer past Krul in the 65th minute.
Huge chances went begging at both ends within a minute, as first Lambert failed to get enough power in his close-range header and then Remy blasted high and wide when he had only Gazzaniga to beat.
Referee Mike Jones required some treatment in the closing stages after Moussa Sissoko accidentally struck him in the face, and tensions flared between both benches late on in a dramatic finish to the game both on and off the pitch.