Cisse thumped a 71st-minute volley past former Magpies keeper Shay Given to settle a game in which the visitors enjoyed the better of the first half, but could not make the most of their chances.
Cisse, who was introduced as an early replacement for the injured Leon Best, saw his Senegal team-mate Demba Ba fire the home side into a 30th-minute lead but, after Darren Bent had twice been denied by keeper Tim Krul, Robbie Keane levelled deep into first-half stoppage time.
However, Alan Pardew's men improved after the break and, to the delight of a crowd of 48,569, managed to see out time to bank another three points.
Newcastle ran out determined to reclaim the fifth place into which they had climbed as a result of Wednesday night's hard-fought victory at Blackburn, and with Ba back in harness.
He was to be joined within 14 minutes by new signing Cisse in what was to prove an eventful first half.
Villa lost the corresponding fixture last season 6-0, and they returned in determined mood this time around.
Bent may not have enjoyed the best of fortunes on his visits to Tyneside with former club Sunderland - his reception was entirely predictable - although he might have silenced the boo boys with 13 minutes.
Keane's pass put him in behind full-back Danny Simpson and Krul did well to save from a tight angle before fielding Stiliyan Petrov's well-struck follow-up less than comfortably.
In the meantime, Best had left the field having been hurt in a block tackle with Stephen Warnock and was replaced by Cisse, who arrived to rapturous applause.
The 26-year-old tested Given with a flicked 16th-minute header, but it was the visitors who continued to enjoy the better of the half with Bent once again denied by Krul after being played in by central defender Richard Dunne.
However, the first goal eventually arrived, against the run of play, at the other end, and the identity of the scorer was no surprise.
Dunne got up well to head Danny Guthrie's cross away from Ba, but when Ryan Taylor smashed the ball back across goal, the former West Ham frontman thumped it past Given to claim his 16th goal of the season.
But as the celebrations broke out, the medics rushed on to the pitch to tend Taylor, who had been hurt in a collision with Warnock in the build-up and left the field on a stretcher with his right leg in a brace.
Charles N'Zogbia fired into the side-netting and Stephen Ireland curled an effort just wide as Villa continued their quest for an equaliser.
However, Ba, full-back Davide Santon and Cisse might all have increased Newcastle's lead in a flurry of activity at the end of the half.
But the game's second goal eventually went the way of the visitors in the fifth minute of stoppage time when Keane met N'Zogbia's cross unopposed in front of goal to volley home.
Villa boss Alex McLeish replaced Ireland with Barry Bannan at the break, but saw his side almost concede the lead for a second time within two minutes of the restart.
Given, who played with such distinction for Newcastle over 11 and a half years, uncharacteristically fumbled after Guthrie had crossed, but neither Ba nor Cisse were able to take advantage.
The game was becoming increasingly open with N'Zogbia for the visitors and Taylor's replacement Gabriel Obertan for the home side enjoying acres of space.
The former Manchester United man worked his way into a promising position with 55 minutes gone when he isolated Dunne and created space to shoot, but he sliced his effort well wide.
Cisse's first big chance arrived with 62 minutes gone and this time from the left when Guthrie clipped the ball invitingly towards him, but the striker could only lift his header over the bar.
Villa eventually responded and, as N'Zogbia made way for Emile Heskey, briefly relieved the pressure.
However, Newcastle regained their lead with 19 minutes remaining, and did so in style.
Jonas Gutierrez's left-wing cross was too high for Ba, but it fell nicely for Cisse to control with his chest before dispatching a left-foot volley high to Given's right.
James Perch drilled a long-range effort just wide and Given had to turn away another Cisse volley, but Krul managed to beat away Ciaran Clark's missile before gratefully grasping substitute Gary Gardner's point-blank header to preserve his side's lead.
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