Undaunted, the world number three took advantage of benign morning conditions to compile eight birdies that left him two shots behind American leader Denny McCarthy.
McCarthy also played in the morning on a day when the late starters battled more demanding weather in a northerly afternoon breeze.
Local hero Jordan Spieth, who next week has a chance of completing the career grand slam of all four majors, shot 68 in the afternoon.
Spieth has played the course hundreds of times and knows every subtle nuance. Not so with Koepka.
"Didn't see the front nine, so I'm pretty pleased with the way I played," Koepka said.
"It's a bit different when you're playing it blind. Kind of don't know where you're going. Relying a lot on the (yardage) book. I never look at the book."
Koepka, winner of three major titles in the past two years, is using the Byron Nelson to tune up for the PGA Championship at Bethpage next week, his preparation a contrast with most of the big names who are taking the week off.
"I just want to strike the ball well," he said. "Obviously the goal is to win but if you don't you just want to feel good leaving for next week."
McCarthy's 63 was even better than it might look at first glance, because he double-bogeyed his fourth hole before roaring back with 10 birdies.
"I told myself I was going to be aggressive today and I wasn't starting off," said McCarthy, making his 43rd start on the PGA Tour.
"The double-bogey helped calm me down in a way. I made a timid swing off the tee. From there on I told myself I was going to play carefree and be really be aggressive."
Australian world number 22 Marc Leishman withdrew before the round, citing a back injury.
(Reporting by Andrew Both in Cary, North Carolina; Editing by Frank Pingue/Nick Mulvenney)
