The Irishman, who won the U.S. Senior Open for the second time last month, birdied the 18th on the Old Course at Sunningdale for the second day in a row to card a second successive 65 and reach 13 under.
American Justin Leonard emerged from a congested leaderboard to card a 65 of his own to be his nearest challenger.
Both Harrington and Leonard are bidding to emulate Bob Charles, Gary Player, Tom Watson and Darren Clarke as just the fifth player to win The Open Championship and the ISPS HANDA Senior Open.
Thomas Bjørn is solo third at ten under after a 67, with Steven Alker, Greg Chalmers and American duo Clark Dennis and Kevin Sutherland two shots further adrift.
Twice a runner-up at the Senior Open, Harrington has spoken this week about not feeling in total control with his game, but he is focused on the challenge that awaits on Sunday.
“I don’t feel very good about how I’m hitting the ball,” he said. “So trying to get away from that and not worry so much about that because clearly I’m scoring well.
“Better off shooting 13-under par and not feeling so good about it than thinking you’re swinging it great and being level par.
“So, I just need to go out and play and try golf tomorrow. Hit the right shot at the right time and not necessarily try and play swing.”
Harrington was initially slow out of the blocks before a stellar tee shot at the par three fourth resulted in a birdie, before he birdied the ninth for the third day in a row to hit the turn in 33.
As earlier cloudy skies and a brief, sharp shower cleared to leave a sunny afternoon, Harrington cancelled out a birdie at the 11th with his lone bogey of the round at the 12th – his first dropped shot since the 18th in the first round.
With Leonard, playing a few groups ahead putting together a solid round, Harrington holed a long-range birdie at the par three 13th before taking advantage of the par five 14th.
A battling par save at the long par three 15th followed, before he showed his class with a brilliant approach from the rough to set up a closing birdie and double his overnight lead.
Like Harrington, Leonard arrived at the fifth and final senior major of the year on the back of playing at last week’s Open Championship at Royal Portrush.
Having played all four rounds in Northern Ireland, confidence in his game was not in short order and he too will go into the final day on the back of a second consecutive 65.
Starting the day at six under, he made four birdies on the front nine, with his sole blemish coming at the second.
He would birdie the 11th, before recovering from a bogey at the 13th with a two-putt birdie at the scoreable 14th, before he became just the third player of the day to birdie the 16th.
While Harrington was unwilling to look too far ahead to the possibility of joining a select group of players to have won both the Claret Jug and Senior Open trophy, Leonard said it would be “very special”.
“To be in contention is something I shoot for every week, and I think we all do,” said the 1997 Open champion.
“To do it in a major championship then is another thing, and then to do it at the Senior Open here at Sunningdale, it’s been a special three days.”
Bjørn is bidding to win his first senior major title, having won for the first time on the PGA TOUR Champions last month alongside fellow former Ryder Cup Captain Clarke.
The Dane was one under for his front nine after mixing three birdies with two bogeys, before birdies at the 11th and 14th helped him keep up with the pace being set by Harrington and Leonard.
A dropped shot at the 15th would follow, but he capitalised on a good approach at the 17th for his 18th birdie of the week.
“A couple too many bogeys, really, I guess,” he reflected. “Six birdies is good enough. Today we played the golf course, at some stage tomorrow, we might have to play the man. That’s the way it’s got to be.
“I’m pretty happy. 67 around here is always a decent score, and you know, leaves me in with a chance tomorrow. But got to have a low one tomorrow.”
Defending champion KJ Choi fell out of contention with a 75 to leave him at two under heading into the final round.
