The 30-year-old Australian, whose resume includes a victory at the 1996 Indonesian PGA Championship and a pair of European Challenge Tour wins, fired a 65 Thursday at Indian Wells Country Club for a 15-under-par 129 total.
Senden started the day tied for third after opening with an 8-under 64 at PGA West's Palmer Course. He remained bogey-free headed into his third round at the Tamarisk Country Club layout.
Overnight co-leader Brandel Chamblee finished alone in second at 14-under after a 67 at Bermuda Dunes Country Club, one of the four courses being used this week for the five-round, 90-hole tournament.
Jay Haas, tied with Chamblee after a first-round 63, also toured Bermuda Dunes Thursday and carded a 68. He stood tied at 13-under 131 with Phil Mickelson, who is making his first start since the WGC-NEC Invitational last August.
Mickelson, the second-ranked player in the world, posted six birdies and one bogey en route to a 67 at Bermuda Dunes.
Senden birdied both par-5s on the front nine and added two more birdies to make his way out in 4-under 32. He gained another stroke at the par-4 12th, where he knocked a sand-wedge approach to the green then rolled in a four-footer to climb to 13-under.
After parring the next five holes, Senden found the fairway at the par-5 18th and hit his 4-iron second shot into a trap on the right side, about pin-high. He then blasted out of the sand and into the cup for sole possession of the top spot.
'The eagle on 18 was the hole of the day,' Senden said. 'I just splashed it out and it dropped right in the middle. I was a happy man.'
Senden is playing in just his second PGA Tour event after receiving exempt status for his fifth-place tie at Q-School in December. He missed the cut in his first start, at last week's Sony Open in Hawaii.
His two 1998 triumphs on the Challenge Tour - Europe's version of the Buy.Com Tour - earned him a place on the main circuit over there.
'I've been playing the last four years in Europe, and that's possibly why my ball-striking has always been there, but never really had many good scores on the board,' said Senden, whose best showing on the European Tour was a tie for fourth at the 2000 Open de France. 'But the last 12 months or 18 months I've really improved my putting, and that's given me a better consistency and better scoring.'
Senden's work on the greens has certainly been a key thus far this week; he is currently tied for first in putting with an average of 24.5 putts per round.
Chamblee's total of 130 marked the lowest 36-hole score of his career. He notched his previous best of 131 en route to his lone PGA Tour victory at the 1998 Greater Vancouver Open.
'Obviously, I'm pretty happy with where I'm at,' he said. 'Who knows what the scores are going to be here the next couple of days, 30-under, who knows? I haven't given any thought to an ideal target score.'
Low scores are the norm at the Bob Hope, due mainly to relatively easy course set-ups for the gaggle of celebrity amateurs who take part each year. Last season, Joe Durant established the record for the lowest score ever in a 90-hole event with his winning total of 36-under 324, breaking the mark of 35-under 325 set here in 1993 by Tom Kite.
Mickelson's 131 matched his career-best two-day total. Although the talented lefthander has shown little rust from his nearly five-month hiatus from tournament play, he did close with a bogey and birdied only one par-5 on Thursday.