Newcastle are currently six points behind the former Heineken Cup champions - and with Wasps not playing until Saturday, when they entertain London Irish, Gary Gold's side can crank up the pressure on their fellow strugglers with a fourth successive home win.
Having served his one-match ban, Adriaan Fondse returns to the second row, while Samoa international Taiasina Tu'ifua gets the nod at blindside flanker.
Mark Wilson drops to a forward-heavy bench - with first appearances for new signings James Goode and Adam Balding.
Meanwhile, hooker Rob Vickers will bring up a century of appearances for the Falcons in the encounter.
"If we front up and stick to our game-plan and we execute things to the level that we are striving for, hopefully the scoreboard will be in our favour," said Gold.
"What Conor O'Shea has built at Harlequins is incredible considering his side came back from relegation just a few years ago.
"I can only imagine what a fantastic environment it must be down at Harlequins."
Harlequins will be buoyed by the inclusion of Mike Brown and Danny Care for the tough trip north.
Brown is free to play after he was released by England, while Care gets the nod ahead of Karl Dickson after starting the defeat to Gloucester on the bench.
Luke Wallace and Chris Brooker also come into the starting XV, with Will Skinner joining Dickson on the bench and Joe Gray ruled out through injury.
Newcastle: 15 Greg Goosen, 14 Tom Bedford, 13 Jamie Helleur, 12 James Fitzpatrick, 11 Jeremy Manning, 10 Jimmy Gopperth, 9 Chris Pilgrim, 8 Ally Hogg, 7 Will Welch, 6 Taiasina Tu'ifua, 5 Tim Swinson, 4 Adriaan Fondse, 3 Euan Murray, 2 Rob Vickers, 1 Grant Shiells.
Replacements: 16 Michael Mayhew, 17 Jonny Golding, 18 Ashley Wells, 19 James Goode, 20 Mark Wilson, 21 Adam Balding, 22 Will Chudley, 23 Alex Tait.
Harlequins: 15 Mike Brown, 14 Tom Williams, 13 George Lowe, 12 Jordan Turner-Hall, 11 Ugo Monye, 10 Nick Evans, 9 Danny Care, 8 Nick Easter (c), 7 Luke Wallace, 6 Tom Guest, 5 Tomas Vallejos, 4 Olly Kohn, 3 James Johnston, 2 Chris Brooker, 1 Joe Marler.
Replacements: 16 Rob Buchanan, 17 Mark Lambert, 18 Tim Fairbrother, 19 Pete Browne, 20 Will Skinner, 21 Karl Dickson, 22 Rory Clegg, 23 Matt Hopper.
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