Spieth was flawless on the penultimate day, blitzing the field with a nine-under-par 63 at the Isleworth Golf and Country Club in Florida on Saturday.
The 21-year-old American, who took out the PGA Tour of Australia's Australian Open in Sydney last week, is 20 under through 54 holes - a tournament record.
Spieth is seven shots clear of compatriot Keegan Bradley (65) and Swede Henrik Stenson (68).
After beginning the day with a par to complete his second round that was cut short due to darkness on Friday, Spieth posted a superb round.
Spieth birdied each of his first three holes in the third round and added another at the seventh as he made it to the turn in a four-under 32.
The Dallas native, who tied for second at the Masters Tournament in April, was even better on the back nine.
Spieth tapped in for birdie at the par-four 10th hole before a run of three consecutive birdies starting at the 12th saw the American sensation take a stranglehold on proceedings atop the leaderboard.
He capped a remarkable day by birdying the final hole, draining a 45-foot putt.
Bradley only dropped one shot en route to his lowest round of the tournament, holing eight birdies to be tied alongside Stenson, who recovered from a slow start to make it through the back nine bogey-free.
Meanwhile, Tiger Woods - host of the 18-man event - remains 20 shots adrift at the bottom of the leaderboard, despite a third-round 69.
Woods had to contend with illness - suffering from a fever and nausea - but the 14-time major winner still managed to end the day with three successive birdies.
American Patrick Reed is nine shots off the pace following his three-under-par 69.
Englishman Justin Rose (70) is a shot further back, while Australian Jason Day (70) is eight under through 54 holes.
Graeme McDowell (68) of Northern Ireland and American trio Matt Kuchar (70), Rickie Fowler (72) and Bubba Watson (72) are all level at seven under.