The contest at the Amex Stadium was settled by Andrea Orlandi and Will Hoskins, with the out-of-form and badly below-par Magpies, who were beaten 1-0 by the Seagulls in the fourth round of the competition last term, seeing captain Shola Ameobi harshly dismissed just after the hour mark.
It was an enterprising and energetic start from Brighton, with James Perch forced to head away from danger from under his own crossbar in the opening 10 minutes, after Liam Bridcutt superbly kept the ball alive on the right before crossing to the far post for Gary Dicker to nod back across the face of goal.
Back-up goalkeeper Rob Elliot, named in place of Tim Krul as one of manager Alan Pardew's five changes, then had to be alert to pluck the ball out of the air on the edge of his six-yard box after David Lopez had drilled a cross into the danger area.
It took until the 21st minute for the Magpies to mount an attack of note as Gabriel Obertan showed good purpose to burst into the box only to waste his attempted cross, before Gael Bigirimana fizzed in a powerful strike which warmed Casper Ankergren's hands before the keeper grabbed it at second attempt.
But just as the Magpies looked to be getting to grips with the game, Brighton took the lead in the 33rd minute thanks to a moment of magic from Orlandi.
Gordon Greer's raking cross-field pass out of defence into the corner was superbly kept alive by Wayne Bridge, who crossed for Orlandi. The Spanish midfielder's first touch flicked the ball into the air and the second, with the outside of his left foot and with his back to goal, diverted it beyond Elliot and into the bottom corner.
Pardew took action following a limp opening 45 minutes from his side with Mehdi Abeid and Perch making way for Nile Ranger and Paul Dummett, but Brighton were again the first to threaten as Orlandi blazed over from a promising position outside the box.
Ranger had a brief sight of goal after Shola Ameobi flicked on in the box, only to completely get under his shot and blaze the ball high into the stands, prompting widespread jeers from the home faithful.
And Newcastle's task become significantly harder in the 63rd minute with skipper Shola Ameobi, who had been booked in the opening moments of the second half, shown a harsh second yellow card and subsequent red after catching David Lopez, with the Brighton man making the most of any minimal contact.
The Magpies actually proved a greater threat when down to 10, with Bridcutt producing a great block to deny substitute Sylvain Marveaux and Ranger heading the resulting corner over, before Ankergren clawed away a cross from Sammy Ameobi which had deflected off the outstretched knee of Greer.
But they were always liable to the counter-attack as the clock ran down with David Lopez sending a precision pass through the visitors' defence in the closing stages for Hoskins to run onto and fire a cool low finish under Elliot in the 87th minute.