Kieron Dyer scored twice, the second of them a spectacular solo effort, as Newcastle cruised unexpectedly easily into the fourth round.
Newcastle had Jonathan Woodgate and Dyer fit again and both made important contributions to Newcastle's victory.
Woodgate helped keep a tight rein on James Beattie while Dyer's pace caused Southampton plenty of problems.
United went ahead in the 24th minute through Dyer and never looked back. Aaron Hughes crossed from the right and Nolberto Solano touched on for Dyer to score with a right-foot shot from ten yards.
Alan Shearer, desperate to win the FA Cup as the end of his career nears, should have added another after 30 minutes but shot over the bar from twelve yards although he did not need to worry.
In the 39th minute Solano took a corner on the left and when it was only half cleared by the defence, Laurent Robert smashed home a left-foot shot from 15 yards.
Saints improved a little after the break and both James Beattie and Claus Lundekvam went close before Dyer made sure there was no reprieve for Southampton.
Picking up the ball near the halfway line, Dyer ran 30 yards at a retreating defence before beating Antti Niemi with a left-foot shot.
Only some wayward finishing by substitutes Lomana LuaLua and Hugo Viana saved Southampton from total humiliation in front of their smallest crowd of the season - 28,456.
Southampton's David Prutton, one of the few home players to play up to standard, was the only player booked in the 79th minute for a foul.
By then Southampton were a well beaten side and memories of their trip to the Millennium Stadium last May for their first final in 27 years were becoming more distant by the minute.