Vaughan, who won the 2008 Senior British Open, played near flawless golf with four birdies in his opening eight holes then added two more in his last four at the Fox Chapel Golf Club.
"I've been hitting the ball pretty good lately. The scores just haven't been very good," Vaughan said. "Today, it just kind of clicked."
Vaughan finished the day one shot clear of Fred Funk and two ahead of Fred Couples, Tom Lehman, Michael Allen and Joe Daly.
"I played pretty solid all day," Funk said. "I had one little hiccup when I missed a little two-footer on 16, but for the first time, you know how people always say, 'You get it back,' and you always believe you never will, but I made a 50- or 60-footer on the next hole, so I got it back.
"And then I made a nice putt on 18. It was really solid, and I'm really pleased with that."
Australia's former world number one Greg Norman was three strokes back and tied for seventh at three-under.