Defending champion Retief Goosen was two shots back after an opening-round 66. Goosen was joined by Trevor Immelman, Markus Brier, Andrew Coltart, Nick O'Hern and Stephen Scahill in a tie for fifth.
Westwood, who won five times in 2000 on his way to the Order of Merit title, has seen his fair share of struggles without a single top-10 finish this season. However, the Englishman, fresh off a solid performance at the Ryder Cup in September, showed signs of his old form at Club de Campo.
'I've worked very hard at home for the last two weeks and I feel it's all coming together,' said Westwood. 'I was looking forward to playing this week and got here early on Tuesday to prepare well.'
He collected three birdies on the front nine and added another at the 10th to move to 4-under. After a birdie at the 12th, Westwood had an eagle opportunity at the par-5 14th, but his putt came up short. Nonetheless, he tapped in for birdie to grab a share of the lead.
Westwood took sole possession of first place at the par-3 17th. He knocked his tee shot within tap-in distance and converted for his best round of the year.
'It's been a long time since I shot a 64,' said Westwood. 'I think this is my lowest score for two years, so it's very satisfying. I've worked hard for it.
'I've been working hard for the last two years, but golf is a strange game. Sometimes you just need to find the key and the confidence can come back as quickly as it left.'
Harrington, who is looking to dethrone Goosen as Order of Merit champion, picked up his first birdie at the fourth and added another at the eighth. He ran home three consecutive birdies starting at the 10th before a birdie at the 15th for a round of 65.
Goosen, who became the first South African to win the Order of Merit with a victory at this event last year, currently leads the European Tour money list.
Adam Scott, a two-time winner on tour this season, had seven birdies and three bogeys to finish three shots back at 4-under-par 67. Scott was joined by Roger Chapman, Diego Borrego, Carlos Balmaseda, Sam Torrance, Christopher Hanell, Patrik Sjoland and Marten Olander.
Fredrik Jacobson, Gary Orr, Anders Hansen, Graeme McDowell, Tomas Jesus Munoz, Henrik Nystrom, Jorge Berendt, Steen Tinning, Jose Rivero, Anthony Wall and Gary Evans are tied at 3-under-par 68.
Seve Ballesteros, a three-time winner of this event, withdrew before the start of the tournament due to the death of his mother. Ballesteros was replaced in the field by Peter Fowler.
Full-field scores from the Telefonica Open de Madrid