The Argentine midfielder - who missed much of the season after suffering from testicular cancer - sent St James' Park into raptures with the goal that sealed a precious victory
Newcastle went into the game knowing a defeat or a draw at St James' Park and a victory for Hull City over Manchester United would see them relegated to the Championship.
But Sissoko's emphatic header and a deflected strike from Jonas late on guaranteed their safety regardless of results elsewhere.
Newcastle head coach John Carver said it would be unthinkable to take his hometown club into the second tier and he was able to savour a victory in what may be his last game in charge.
Unpopular owner Mike Ashley broke his silence before the game to vow that the club is not for sale at any price and he is going nowhere until Newcastle win a trophy, but was giving nothing away over who will be manager next season.
While Carver's tumultuous reign looks set to come to an end, former Newcastle boss Sam Allardyce has taken charge of West Ham for the final time as the club have confirmed he will not be offered a new deal.
Newcastle's leading scorer Papiss Cisse made his first start since early March, while Mike Williamson and Vurnon Anita were also recalled as Ayoze Perez, Ryan Taylor and Remy Cabella dropped to the bench.
Allardyce made two changes to his starting line-up, with former Newcastle captain Kevin Nolan and Reece Burke replacing the injured Mark Noble and James Collins.
IN PICTURES The final day of the 2014-15 Premier League season
Newcastle made an encouraging start and Emmanuel Riviere was presented with a great chance to put them in front inside a minute, but snatched at his shot from close range.
Enner Valencia wanted a penalty when he went down in the area moments later, but Williamson did not appear to make any contact and referee Martin Atkinson waved play on.
Riviere acrobatically volleyed into the side-netting and Daryl Janmaat dragged a strike wide of the far post as Newcastle attempted to ease the tension.
Newcastle's hearts were in their mouths when Stewart Downing raced into the penalty area 23 minutes in, but Tim Krul denied the winger what would have been a controversial goal given he was marginally offside.
The home supporters becoming increasingly edgy as their side failed to open the scoring in a frantic first half, but knew Hull were also being held by United.
Riviere had another golden opportunity to make himself a hero five minutes into the second half, but somehow failed to make contact with Janmaat's cross from around six yards out.
St James' Park erupted just four minutes later, though, when Sissoko met Gutierrez's fine cross from the left with a downward header to put Newcastle in front.
Gutierrez then raised the roof by unleashing a strike that deflected beyond Adrian and celebrated in style as Newcastle ended the season on a high note.