The 43-year-old Campbell holed a 10-foot birdie at the last for a 6-under 64 that gave him a one-stroke lead at 9 under on the Fanling course at Hong Kong Golf Club.
Four other 40-somethings followed Campbell on the leaderboard. Miguel Angel Jimenez of Spain, 48, posted a 67 to share second with Lian-Wei Zhang of China, 47, and Fredrik Andersson Hed of Sweden, 40, who both shot 66.
And 42-year-old Anders Hansen of Denmark matched Campbell's 64 to sit fifth at 7 under.
Campbell denied Tiger Woods the 2005 U.S. Open title at Pinehurst, and hasn't tasted success since winning the World Match Play Championship at Wentworth four months later.
He was surprised to learn McIlroy missed the cut with a 5-over total.
"It now makes winning the Hong Kong Open a lot easier, definitely," Campbell said. "But then Rory's world No. 1 for a reason as he's a wonderful talent and I've admired him ever since he turned pro."
The New Zealander based in Spain was third in the Portugal Masters a month ago, his best result in years. He confessed there were occasions since his last win, after which he became distracted by off-course events, that he considered quitting golf. But he gained inspiration from the winning efforts of fellow 40-somethings.
"You can't buy confidence, you just have to earn it, and I think I've earned it over the last seven years since I haven't won a golf tournament," Campbell said.
"There have been times where I wanted to throw it in, but what's really inspired me over the last, particularly over the last four or five years, is seeing my friends around the same age bracket as me, the 40-plus club.
"The likes of Ernie (Els) winning his fourth major, Thomas Bjorn winning three times last year. Paul Lawrie's had a wonderful last couple of years. Padraig Harrington, he's 40 now. Jim Furyk winning the FedEx Cup. And the list goes on.
"So being 40 isn't that bad playing golf, and seeing my friends win tournaments left, right and center definitely inspired me to don't give up and keep on playing."
McIlroy double-bogeyed his last hole in a round of 72, following a 73 to open his title defense.
"It's disappointing as you never want to miss the cut and even more when you are defending a tournament," he said.
"So it's not the week I wanted but then I have a few days to work on my putting and try and get ready for (the Tour Championship in) Dubai."