The Swede, who has won 11 times on the European Tour, seemed to have a rare case of 'the yips' that saw him struggling to pull the club back from the ball.
The movement disorder - known as 'the yips' in golf circles - is usually associated with putting, but the exact cause of Karlsson's ailment is unknown.
The 42-year-old played just two holes in his practice round before deciding to leave the course and pull out of the tournament.
“Have got into some bad habits in my game and routine that I need to address. Taking a few weeks off," Karlsson said on Twitter.
Luke Donald's caddie John McLaren was on the course when Karlsson's game fell apart and admitted it was an odd sight.
"’It was probably the worst case I have ever seen and you felt so sad for Robert. We can only hope he finds a solution quickly," he told the Daily Mail.
Sergio Garcia, who has had his own struggles in the past, was also playing with Karlsson at the time. He put his arm around the Swede and they had a 10-minute conversation before Karlsson walked off.
Karlsson has been ranked as high as sixth in the world and played for the European Ryder Cup team in both 2006 and 2008.
He has also finished in the top eight of all four Major championships and won the European Tour Order of Merit in 2008.