Alberto Zaccheroni's men went in a goal down at half-time after Frank Acheampong opened the scoring for the visitors midway through the first period.
However, Japan responded in style after the interval and eased to victory thanks to strikes from Shinji Kagawa, Yasuhito Endo and Keisuke Honda.
Ghana went into the game at the Saitama Stadium 2002 after securing a vital FIFA World Cup qualifying win over Zambia last Friday - a result that secured their place in the final play-off round as they look to reach Brazil 2014.
And, even though only three of the side that started the fixture in Kumasi began this game, Kwesi Appiah's side looked full of confidence and went ahead after 24 minutes through Anderlecht striker Acheampong.
Japan, who have already secured their place at next year's World Cup, struggled to assert themselves in the first half, but came out with all guns blazing after the break and deservedly drew level just five minutes after the restart.
Manchester United playmaker Kagawa cut inside from the left wing and hit and hit a low drive past the despairing dive of Razak Brimah from 20 yards.
And it did not take long for Zaccheroni's team to edge ahead, as Endo and Honda exchanged a neat one-two before the Gamba Osaka man curled a shot from the edge of the area that squirmed under Brimah just after the hour.
By this point, the hosts were rampant and Endo and Honda combined again to increase their advantage just four minutes later, as the former swung in a free-kick and the latter glanced a header home from eight yards.
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