The Ghanaian defeated Sissoko, who was representing current club Tottenham Hotspur, courtesy of a last-minute Jonjo Shelvey winner to seal a place in the last eight of the competition.
How it unfolded
After a cagey opening, it was Atsu's Magpies who got off the mark first as Joelinton - who scored against Spurs earlier this season in the Premier League - netted with a close-range finish at the Gallowgate End.
In a second half full of chances, Sissoko got his name onto the virtual scoresheet through his own on-screen likeness; turning the ball home from six yards following a save by Martin Dúbravka.
But with the game looking set for a 'golden goal' period, Atsu took the spoils with an 89th-minute Jonjo Shelvey header to set up a quarter-final tie against Liverpool's Trent Alexander-Arnold.
Next round
You can watch Atsu in EA Sports FIFA 20 action against Trent Alexander-Arnold LIVE from 12pm on Friday 24th April on Sky Sports' YouTube and Twitch accounts, as well as on online Premier League channels, including Twitter.
Other results
Alexander-Arnold secured his quarter-final place against Atsu with a 5-1 victory over Manchester United, who were being represented by singer Tom Grennan.
Elsewhere on Wednesday, Everton's André Gomes produced one of the shocks of the tournament so far, demolishing Chelsea's Reece James 8-0.
Meanwhile, Manchester City's Raheem Sterling narrowly progressed after a 5-4 victory over Crystal Palace's Wilfried Zaha.
Tournament standings
The online tournament features representatives from all 20 Premier League clubs, with each competitor taking part in a knock-out style cup competition from the comfort of their own living rooms.
John McGinn (Aston Villa), Nathaniel Chalobah (Watford), Ryan Fredericks (West Ham United) and Angus Gunn (Southampton) were all eliminated in Round 1.
Here are the latest standings (updated 5pm, Wednesday 22nd April):
About the ePL Invitational
The ePL Invitational tournament is operated by esports tournament organisers Gfinity.
For more information, please visit premierleague.com/epl-invitational.
