The Northern Irishman, who is yet to win the British major, sunk six birdies in what he described as "the perfect round" to give him a narrow advantage over Matteo Manassero on a good day for the Italian contingent.
Compatriots Edoardo and Francesco Molinari shot 68s - the latter courtesy of an eagle-three at the last - while Tiger Woods, who won the last time the event was hosted at Hoylake, recovered from a poor start to finish at three under.
Phil Mickelson's title defence began with a whimper, though, as the left-hander carded bogeys at the 13th and 14th to fall seven shots off the pace, while fellow Americans Jim Furyk and Brooks Koepka joined the Molinaris on four under.
In-form home favourite Justin Rose, who has won his last two tournaments, endured an inconsistent round before signing for an even-par 72, with playing partner Adam Scott eagling the fifth en route to 68.
World number one Scott, who scrambled to save par at the last after two wayward shots, is seeking to exorcise his Open demons of 2012, when a dropped shot at each of the final four holes handed the title to Ernie Els - who suffered a nightmare of his own on Thursday.
The South African, a two-time winner, three-putted at the first hole from no more than two feet; his triple-bogey seven setting the tone for a miserable 79.
Woods looked as though he may be on his way to a similarly poor score when he bogeyed the first two holes, but the 14-time major winner hit five birdies on the back nine to earn a tie for 10th.
Rookie Ashley Chesters settled any early nerves with a birdie at the first on his way to finishing two under, but fellow amateur Neil Bradley ended up equalling Els' tally on a day to forget.
The worst score was registered by Australia's Bryden Macpherson, whose round of 90 included an eight at the par-four 12th.