Spieth posted a seven-under-par 63, grabbing his eighth birdie of the round on his last hole at TPC River Highlands in Connecticut, to make an immediate impact on his debut in the event.
He leads by a shot from two fellow Americans, Johnson Wagner and Brett Stegmaier, after they had carded matching 64s in the morning wave at the venue in Cromwell.
On a day when Rory McIlroy opened with a 67, Knox signed for a 69 while Martin Laird had to settle for a 72.
“It was a really solid start,” said two-time major winner Spieth, who hadn’t been firing on all cylinders as he finished in a tie for 35th in last week’s US Open at Erin Hills.
“I got things kicking off early and that helps you walk a little easier and helps with the shots you’re playing throughout the round.
“You don’t feel like you have to take as many chances and I was able to play away from some pins when I was in a little bit of trouble.
“You’re not going to shoot seven-under every round, it’s impossible and I recognise that, so it’s about waiting for my chances to come in the same way we did today.”
Stegmaier, a Connecticut native who has missed the cut in eight of his last 10 tournaments, reeled off seven birdies in a nine-hole stretch in the middle of his round.
Knox signed for three birdies, including back-to-back at the 15th and 16th, as he found himself sitting joint-51st after the opening round.
Laird, who was the sole Scot out of three starters to make the cut in the US Open, was four-over on the back nine, as he left himself facing a fight to make the cut in 111th position.
Bidding to end a miserable run of 14 consecutive missed cuts this season, Scott Henry is leading Scot heading into the second round of the BMW International Open in Munich.
It followed the Clydebank man signing for a three-under-par 69 on a day when Australian Wade Ormsby opened with a 64 to set the pace.
Scottish interest in this year’s Amateur Championship ended as Swede Fredrik Nielhen produced a brilliant finish to beat Robert MacIntyre, the losing finalist 12 months ago, at Royal St George’s.
MacIntyre, a left-hander from Glencruitten, had fought back from being two down after six holes to lead by the same margin with five holes to play before his opponent squared the last-16 tie with birdies at the 14th and 15th.
The Scot got his nose in front again when a par proved good enough to win the short 16th only for Nilehn to finish birdie-birdie, ending MacIntyre’s hopes of going one better in the amateur game’s blue ribbon event.
His exit came after compatriot Ryan Lumsden had also bowed out in the fourth round, the Royal Wimbledon player letting slip a two-hole lead at the turn as he lost by two holes to Norwegian Jarle Kaldestad Volden.
Earlier, Peebles player Craig Howie, the third Scot to make it into the last 32, had lost at the 20th to another Norwegian, Kristoffer Ventura, in the third round.
Downfield’s Graham Bell sits atop a crowded leaderboard heading into the final round of the Scottish Seniors Open Championship at Royal Burgess.
Bell, last year’s Scottish Seniors Order of Merit winner, added a 73 to his opening 66 for a three-under-par total, one ahead of Englishman Stephen East (68-72) with two other raiders from south of the Border a further stroke back.
Sitting five behind Bell, Blairgowrie’s Tom McLevy (70-72) is still in the reckoning, as is host club player John Fraser after rounds of 74 and 70.
Senior Tour debutant Gary Orr is lying joint-10th, six behind leader Santiago Luna, after two rounds in the European Tour Properties Senior Classic in Finland.
Orr backed up his opening 71 with a 70 for a three-under-par total, giving himself an outside chance of making a winning start on the over-50s circuit heading into today’s final round.
Jack McDonald fared best of the Scots with a two-under 70 in the opening round of the Made in Denmark Challenge.
The effort left him sitting six shots off the lead, held jointly by Austrian Manuel Trappel and South African Thriston Lawrence.
Englishman Chris Lloyd, last week’s winner at Montrose, shares the lead on 14-under heading into the final round of the PGA EuroPro Tour’s PDC Championship at Studley Wood.
The first-round pace-setter was joined in top spot by compatriot James Ruth after he carded a 64 in the second circuit.
Leading Scots, both sitting nine shots off the pace, are Craig Lawrie and Louis Gaughan.