He shot to limelight in the Under-19 World Cup in Dhaka which saw him showcase his free-flowing batting style to help India to a victory against Sri Lanka. He backed up that performance with a series of good shows in the domestic circuit which got him in contention for national selection. 

He made his ODI debut in 2004 and his Test debut the same year against Australia. However, he did not have the best of times as he managed just one half century in a span of ten Test matches, his highest being 93 against Pakistan in Kolkata. The year 2005 proved to be a dry year for Karthik and he next played a Test for India only after two years. His maiden Test hundred came against Bangladesh in Dhaka, but was often out of the Indian squad due to inconsistency and the emergence of MS Dhoni. 

Karthik however continued to churn runs in the domestic circuit and made appearances for India till 2010. He was out of the team for three years until he again got a national call up owing to good domestic performances and incredible showings in the IPL for Mumbai Indians. He proved to be the franchise’s batting mainstay with truck loads of runs which was instrumental in Mumbai Indians claiming the title in 2013. He was then picked in the India squad for the 2013 ICC Champions Trophy in England and played the subsequent ODI series in West Indies and Zimbabwe and the Asia Cup in 2014.