Both carded four-under-par 66, Singh's effort putting him atop the leaderboard at seven-under 133, with Mickelson a stroke back on 134.
Neither Singh nor Mickelson has ever won a WGC event. The absence of Tiger Woods offers an improved opportunity for one of them to break through at this eight million-dollar tournament.
'Two different days,' Singh summed up. 'Yesterday, I drove the ball and couldn't miss a fairway, and today I couldn't find one, so that was a big difference.
'I felt very comfortable on the tee. I just don't know what happened. It just didn't go straight today (but) my iron play was the same and I putted decent.'
Mickelson, meanwhile, was pleased to see improvement in his short game, after disappointing performances at the US and British Opens.
'I feel much, much better with the putter, much better with the wedges,' he said.
'I hit some great wedge shots today, just the basic little chip shots that I expect to get close. I haven't been performing the way I expected, and this week it feels much better. I spent last week on short game exclusively and I feel like it's starting to come around.'
Although Mickelson has not won a WGC event in 24 tries, he has won at Firestone, capturing the 1996 World Series of Golf, which was the forerunner of this tournament.
Out in the first group of the day, he took advantage of perfect morning conditions to pick up five birdies, before dropping a shot at his penultimate hole, the eighth.
He almost squandered another shot at his closing hole, but saved par with a 20-foot putt.
'It was a big putt, because I wanted to go into the weekend with a bit of momentum,' he said. 'I didn't want to bogey the last two, but that putt looked good and I felt I could make it.'
Singh and Mickelson will be paired together in Saturday's third round.
The two clashed at the Masters three years ago, when Singh accused Mickelson of damaging the greens with his long spikes. Singh said he wouldn't be focused on his playing partner.
'I'm going to play my heart out and not really be concerned about how Phil does. He's going to be focused on his game. I hope we both have a good day,' Singh said.
Zach Johnson, Australian Peter Lonard, Sean O'Hair and England's Lee Westwood were two shots off the pace.
Johnson carded a 68, Lonard a 66, O'Hair a 67 and Westwood a 65 to share third on 135.
British Open champion Padraig Harrington fell 11 strokes adrift after a disappointing 75.