The Irishman shot a five-under-par 65 to be eight-under for a one-stroke lead over a hard-charging Thomas Bjorn and defending champion KJ Choi.
The Dane shot a sterling seven-under 63 to catapult into contention, while Choi posted a 67.
Australian Cameron Percy fired a five-under (65) to be on the next line with Justin Leonard (65), South African Ernie Els (67) and Ricardo Gonzalez of Argentina (67) at six under par.
Percy eagled the par-five first on Friday before bookending a birdie at the third with bogeys on holes two and four.
But he finished well with four more birdies to remain firmly in the mix.
Steve Allan (67) is the next highest-placed Australian at five under, one ahead of compatriot Mark Hensby, who followed his 64 with a 72 to fall down the leaderboard at four under.
Compatriot Greg Chalmers (66) is with Hensby with another six others in tied 10th at four under.
Victorian Richard Green (69) and Queenslander Michael Wright (65) are a shot further back, tied 18th and five behind the lead.
After his opening 63 for the overnight lead, New Zealander Steven Alker made a 73 to drop back to four under.
Harrington had five birdies, including at the first and last holes, while keeping his scorecard clean of bogeys.
Harrington is trying to become the fifth player to win the British Open and the Senior British Open.
"I rode my luck a lot today," Harrington said. "Got my head in the game. Did a lot of good stuff mentally. Short game was sharp."
"Hit some recovery shots and managed my game, but I never showed much confidence out there at all in my swing. I obviously like these 72-hole ones, and the bigger golf courses suit me."
The Senior British Open is the fifth major on the PGA Tour Champions. The regular tournaments are 54 holes. Harrington won the US Senior Open at The Broadmoor in Colorado.
The Irishman has already collected two other senior major titles - the 2022 and 2025 US Senior Opens.
Bjorn admitted he was "very angry" with himself over a ho-hum first round, which ended with a double bogey.
Choi could have been higher up the leaderboard if not for consecutive bogeys at Nos. 16-17 taking him down a few pegs.
with AP
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