Wadkins, a two-time winner last season, birdied each of his last four holes after making his second eagle of the round at the par-5 13th. He had been just 2-under through 12 holes.
Mark O'Meara, in his second Champions Tour event, shot a 7-under 65 and shares second place with Allen Doyle and two-time champion Gil Morgan. Argentina's Eduardo Romero and Wayne Levi are one shot further back at 66.
In all, there are 30 players at 3 under or better and 48 who broke par Friday at Quail West.
But they are all looking up at Wadkins, who is enjoying his first 18-hole lead since he posted two during a three-month span last year. The first ended with his win at the Boeing Championship.
Two months later, he won his first major at the Senior Players Championship.
On Friday, Wadkins chipped in from 20 yards for an eagle at No. 1, then three- putted from 30 feet for a bogey at No. 3. He landed a 9-iron within two feet at No. 6 to set up his second birdie.
Wadkins knocked a 3-wood onto the green and made his second eagle at the 13th on a 20-foot putt. He birdied the 15th on another 20-footer, drained a 12-footer at the 16th and then made putts of six and 15 feet to finish off his birdie streak.
'I had a really simple round today. Pain free,' Wadkins said. 'Iron shots that weren't good found a way to find the green.'
O'Meara improved by 17 shots over his final-round 82 in last weekend's Outback Steakhouse Pro-Am, which dropped him into a tie for 38th in his Champions Tour debut.
Friday, O'Meara hit 10 fairways and 16 greens in regulation. He also started out with an eagle at the par-5 first.
'Hopefully I'll play well the next two days,' O'Meara said. 'There's a lot of nice names up there (on the top of the leaderboard).'
Doyle posted his best score at this event since he won in 1999, hitting 12 fairways and 15 greens in regulation and making seven birdies. He opened with three consecutive birdies, the last coming on a 30-foot putt at the third.
Afterward, the two-time defending U.S. Senior Open champion was in a joking mood.
'My daughter is married to the producer of The Golf Channel. Maybe I'll hog all of the TV time tomorrow,' he said.
Morgan, the 1998 and 2001 champion, carded his best-ever score at this event and has now posted a sub-par first round in Naples in each of the last nine years.
John Bland, D.A. Weibring, Mark Johnson, Morris Hatalsky, Brad Bryant and Mike Reid share seventh place at 5-under 67.
Defending champion Loren Roberts leads a group of nine players who are knotted another shot further back at 68. Roberts made this tournament his third straight win to begin last season -- a Champions Tour first.