Wilkinson scored six penalties and played with increasing assurance in a performance that should book his ticket on the Lions' plane to New Zealand.
Despite losing, London Irish will return home in good spirits after securing the bonus point they needed to secure their Zurich Premiership status.
The game turned into a kicking contest between fly-halves Barry Everitt and Wilkinson, with the England captain coming out on top. Irish started the brighter of the two sides, with former Leicester flanker Paul Gustard prominent in the loose.
They were rewarded for their early dominance with a try for winger Delon Armitage after just five minutes.
The Irish forwards controlled the ball through several phases before the ball was fed to Gustard, who timed his pass to perfection for Armitage to crash over in the corner.
Everitt's touchline conversion made it 7-0 to the visitors.
Newcastle responded with a 50-metre Wilkinson penalty, but Irish continued to dominate and centre Nils Mordt was held up over the line after a break by Paul Hodgson.
Hodgson was again involved on 20 minutes when he made space for Scott Staniforth down the left. Full-back Michael Horak carried the ball on certain but a last-ditch double tackle from Matthew Burke and Colin Charvis somehow prevented the score.
The Falcons had a try of their own disallowed after 32 minutes when a jinking run by Wilkinson set up field position in the Irish 22. Hall Charlton picked up the quick ruck ball and slid over by the posts only for referee Roy Maybank to penalise the Falcons for crossing.
The Falcons grew in confidence as the half wore on, and number eight Phil Dowson scored a try after Wilkinson cut inside and brilliantly passed out of the tackle. Wilkinson was unable to convert from wide out.
An Everitt penalty either side of half-time made it 13-8 to Irish.
Wilkinson responded with another long range effort after 51 minutes, and another five minutes later as the Falcons edged nervously in front 14-13.
Both sides struggled to play with any fluency although forgotten man Mathew Tait made a couple of sharp breaks for the Falcons.
Everitt had a chance to put the visitors in front but his 66th minute penalty drifted wide of the right post.
Everitt was made to rue his miss as the Falcons reasserted control with two more Wilkinson penalties to make it 20-13.
Everitt replied with a 77th minute penalty but Wilkinson's sixth of the day in the 80th minute made the game safe for the Falcons.
For Newcastle:Tries: BurkePens: Wilkinson 6
For London IrishTries: ArmitageCon: ArmitagePens: Everitt 3
Newcastle Falcons: 15 Matthew Burke, 14 Tom May, 13 Jamie Noon, 12 Mark Mayerhofler, 11 Mathew Tait, 10 Jonny Wilkinson, 9 Hall Charlton, 8 Phil Dowson, 7 Cory Harris, 6 Colin Charvis (c), 5 Stuart Grimes, 4 Luke Gross, 3 Micky Ward, 2 Matt Thompson, 1 Galo Alvarez QuinonesReplacements: 16 David Wilson, 17 Andy Long, 18 Geoff Parling, 19 Mike McCarthy, 20 Mark Wilkinson, 21 James Grindal, 22 Dave Walder
London Irish: 15 Michael Horak, 14 Scott Staniforth, 13 Geoff Appleford, 12 Nils Mordt, 11 Delon Armitage, 10 Barry Everitt, 9 Paul Hodgson, 8 Roland Reid, 7 Kieron Dawson, 6 Paul Gustard, 5 Bob Casey, 4 Ryan Strudwick (captain), 3 Rob Hardwick, 2 Adrian Flavin, 1 Neal Hatley.Replacements: 16 Doug Wheatley, 17 David Paice, 18 Nick Kennedy, 19 Declan Danaher, 20 Kieran Roche, 21 Mark Mapletoft, 22 Kevin Barrett Referee: Roy MaybankTouch judges: Brian Campsall, Steve SavageAssessor: Colin High