McIlroy, whose two previous major wins have been secured by eight-stroke margins, initially found scoring tougher at Hoylake on Saturday, having been four clear at the halfway stage following successive rounds of 66.
The Northern Irishman was briefly joined at the summit of the leaderboard when Rickie Fowler surged to 12 under on the back of seven birdies.
However, Fowler then dropped three shots in the space of four holes to undo much of his earlier good work, while McIlroy followed a birdie at 14 with stunning eagles on the 16th and 18th holes, either side of his third bogey of the day.
McIlroy therefore signed for a 68 and ended the penultimate day in command of the tournament at 16 under, with Fowler, who at least picked up a shot at the final hole, half a dozen behind.
Sergio Garcia, an Open runner-up to Padraig Harrington in 2007, and Dustin Johnson head into Sunday a shot behind Fowler, and France's Victor Dubuisson is eight under after a 68.
Although heavy rain swept in over the Wirral during the early stages of Saturday's play, the forecast thunderstorms - which had prompted organisers to sanction a two-tee start for the first time in Open history - never materialised, meaning conditions were nothing like as severe as many had anticipated.
McIlroy's four-shot overnight buffer was immediately halved as he bogeyed the first for the second day running and saw Johnson make birdie to reach nine under.
Johnson soon faded, but an alternative American threat came from Fowler, who has posted top-five finishes at each of this year's previous majors.
The Californian made gains at four of his first six holes and strung together three birdies in a row from the 10th to move alongside McIlroy.
However, Fowler could not maintain his charge and, as he faltered, McIlroy took full advantage, with outstanding approach play setting up eagle threes at both 16 and 18.
Garcia was able to find five birdies in between dropped shots at the first and 17th, while Johnson showed good character by coming home in 34 to keep his slim victory hopes alive.
World number one Adam Scott also finished strongly, recording five birdies in the final eight holes of his round.
At six under, he was one shot ahead of three other former major winners in Darren Clarke, Graeme McDowell and Justin Rose, who went round in 67, 68 and 69 respectively.
Three-time Open champion Tiger Woods, the last man to be six clear after 54 holes of an Open en route to a record-breaking score of 19 under at St Andrews in 2000, remained way down the leaderboard at three over after carding 73.