Wilkinson has been on the bench for the Falcons' last three matches following his recovery from a groin injury - his sixth comeback since kicking England to World Cup glory in 2003.
The 26-year-old made lengthy appearances in each game, convincing director of rugby Rob Andrew he is ready to play a full 80 minutes.
Wilkinson has been named skipper and will form an all-England midfield alongside Jamie Noon and Mathew Tait.
Andrew said: "It's a bit ironic that it's taken us until the last game of the season to start with the Wilkinson/Noon/Tait axis.
"Clearly we would have loved to play Jonny, Jamie Noon and Mat Tait together for much more of the season.
"But for Noony and Taity they are both keen to go on England's summer tour and Saturday is another chance for them to show what they've got."
Newcastle will make Premiership history on Saturday by becoming the first club to select an all-English 22 for a match.