The world's No. 2-ranked golfer finished with a 3 over par 75 for the day and a 5 over total for two rounds on the West Course at Wentworth.
McIlroy was one of five 2012 European Ryder Cup winners to bow out of the Tour's flagship event — joining two-time defending champion Luke Donald, Ian Poulter, Graeme McDowell and Paul Lawrie.
However, it was a different story for another of Europe's winners at Medinah. Francesco Molinari put himself in position to capture a fourth European Tour title by shooting a 68 in cold, wet conditions to move one shot clear of the field on 6 under.
"I am really happy with my two days and while the conditions were quite tough, I'm hitting the ball well off the tee, and the putter is also working well," the Italian said.
Four players — South African George Coetzee (70), Scotland's Marc Warren (70), England's Mark Foster (69) and Spain's Alejandro Canizares (70) — share second place on 5 under.
Spain's Sergio Garcia (71) put aside controversy earlier in the week after an inappropriate remark about Tiger Woods to be just five shots from the lead at 143.
McIlroy could only manage to hit four fairways in his second round, a roller-coaster front nine of four birdies but also five bogeys. The Northern Irishman steadied to par the next seven holes but then doubled-bogeyed the 17th when he drove out-of-bounds ahead of a two-putt birdie at the last.
It is the second year in succession that McIlroy has missed the cut at Wentworth.
"It was just a tough day and I didn't get off to the best start to be 2 over through 3," McIlroy said. "I did manage a couple of birdies to get back to level but it was a grind.
"I was missing a lot of greens and couldn't really give myself many chances to make any shots back and obviously try to get into the weekend."
McIlroy was undecided as to whether to travel to Paris to see his girlfriend Caroline Wozniacki prepare for the French Open or travel to Monte Carlo for the Monaco F1 Grand Prix.
Donald (72) was 6 over after two rounds and missing the two over par cut by four shots in the miserable conditions.
"Even for England this weather is pretty unseasonal and it made the course play very tough because the last couple of years it's been very warm and the ball has travelled a lot," Donald said. "I was nine over through 21 holes playing pretty terrible golf, really."
Poulter (76) and 8 over is planning to make the most of his free weekend, going to the Champions League final at Wembley Stadium on Saturday and then to the Monaco Grand Prix on Sunday.
"I'm fine. I'm fine," Poulter said. "Don't worry about me as I will be posting some good scores again, soon."
Lawrie was 3 over par with a 72 and McDowell 5 over after a 75.
McDowell's last five tournament results are now: missed cut (Masters), win (RBC Heritage), missed cut (Players Championship), win (Volvo Match-Play Championship) and missed cut (BMW PGA Championship).
"My next tournament is the US Open and I would say my preparation is perfect," he said, laughing.