Cisse netted arguably the best double Stamford Bridge has seen to keep Newcastle in the hunt to snatch one of the final two Champions League qualifying spots.
The striker's 12th and 13th goals since his January move from Freiburg also left Chelsea four points adrift of fourth place with just two league games remaining.
It now looks like they will need to win this month's Champions League final against Bayern Munich to qualify for next season's competition.
Their fate will be sealed if two of Newcastle, Tottenham and Arsenal win this weekend after the Blues contest the FA Cup final.
Defiant Chelsea caretaker manager Di Matteo said: "It's going to be difficult now for us to reach fourth spot.
"We'll keep pushing though until it's impossible. We won't give up."
Despite the sensational turnaround in fortunes Di Matteo has overseen since taking charge two months ago, Chelsea have paid the price for failing to beat any of the teams above them in four head-to-head clashes.
But Di Matteo said: "We've lost many points during this season.
"Looking back over the whole season, that's why we're in the position we are."
The Italian refused to use exhaustion as an excuse, despite his side having played every midweek and weekend since he took charge.
"We've been pushing the players for the last two months and they've responded extremely well," said Di Matteo, who also defended his decision to make six changes on Wednesday night, including resting both Juan Mata and Frank Lampard.
"Tonight [Wednesday], we have to give credit to Newcastle. They did well and played a very good game against us.
"They have a player in their team at the moment that, whatever he touches, it goes in.
"But my players have given everything.
"We've been asking them to push and push and push and they've done well.
"We'll regroup and pick them up. We've got a big game, a great final, on Saturday and we'll go again.
"We'll look forward to the FA Cup final. It's a great event and the motivation is going to be there."