Gil Morgan, who owns 23 Champions Tour wins, and David Eger, a two-time winner on tour, each posted rounds of 4-under-par 68 and share second place.
Six players share fourth place at minus-3. They include - 2005 Toshiba Seniors Classic winner Mark Johnson, 2005 U.S. Senior Open champion Allen Doyle, television announcer Gary McCord, Dan Pohl, Gary Robison and 2002 U.S. Senior Open winner Don Pooley.
Simpson, who is looking for his first Champions Tour win, started on the back nine of the Nicklaus Course at Vista Vallarta Golf Club with three straight pars. He rolled in his first birdie try on the par-4 13th.
The 50-year-old moved to 2 under with a birdie on the 16th. Simpson turned at minus-3 thanks to a birdie on the par-4 18th.
Around the turn, Simpson moved to 4 under with a birdie at the fourth. The seven-time winner on the PGA posted his last birdie on the seventh. He parred the last two holes to close a bogey-free round.
'I played really well,' Simpson said. 'I got a couple of breaks where I missed a couple of bunkers. I didn't have any bogeys, which is a good thing, and I putted well.'
Morgan came flying out of the gate with three straight birdies from the second. However, he bogeyed two of three holes from the fifth to slip to 1 under.
The 59-year-old got back to minus-2 with a birdie on the par-5 eighth. Morgan picked up another birdie on the 11th to reclaim the second lost stroke. He carded his last birdie on the 14th. Morgan parred the final four holes to share second place.
Eger also started on the back nine Friday. He opened with birdies on 10 and 12, but gave one shot back with a bogey on the 13th. Eger quickly atoned for that error with a birdie on No. 14.
The 54-year-old parred five straight around the turn before rolling in a birdie try on the second. Eger parred the next five holes, then birdied the eighth to end at minus-four.
'I struggled some on my front nine today,' said Eger. 'Its a course you need to keep the ball in play. It is a good start, anything in the 60s is good.'
Hale Irwin, the all-time wins leader on the Champions Tour, carded a 2-under-par 70. He stands alongside Morris Hatalsky, Bruce Lietzke, Bill Longmuir, Mike Reid and Mike San Filippo in 10th place. Seven more players are one stroke further back at minus-1.