The 19-year-old Scot, who received a first-round bye, clawed his way back into the second set from 4-1 down but managed to win just one point in a one-sided tiebreak as Novak closed in style.
It was the 10th time this year Murray has tripped up at the first hurdle and came on the heels of his first-round defeat by compatriot Tim Henman in Bangkok last week.
"Every single young player goes through a patch where he's not playing well," shrugged the fourth-seeded Murray, who was in the same half of the draw as world number one Roger Federer.
"You can't expect to get to the semi-finals every week -- unless you're Roger Federer or Rafael Nadal. They are the only two who can do it. I wasn't looking that far ahead."
The fiery Scot also paid tribute to Henman and Novak following his two losses in Asia.
"It's not like I lost to bad players," said Murray. "Henman has been at the top of the game for a long time. Novak was number five in the world (in 2002).
"I did well to fight back into the match but unfortunately I couldn't quite turn it around."
Defending Tokyo champion Wesley Moodie beat Austria's Stefan Koubek 6-3 6-4 to put the South African on course for a third-round meeting with Federer.
The Swiss, making his first appearance in Japan this week, was playing Serbian qualifier Viktor Troicki later on Wednesday in his opening match at the $765,000 tournament.
