Unwell for a while, Mr Mani was hospitalised for the past two days and was battling with liver disease.
Prime Minister Narendra Modi also expressed his grief over the loss.
In a career spanning close to a quarter century, Mr Mani had acted in around 200 films and of late, was seen more often in Tamil films.
A promising career is cut short. Kalabhavan Mani was multifaceted & popular. Pained by his demise. Condolences to his family & fans: PM- PMO India (@PMOIndia) March 6, 2016
Beginning his career as a mimicry artiste, he went on to play serious and even villain roles and was a popular singer too, especially of ballads.
For his brilliant portrayal as a blind man in the film "Vasantiyum Lakshmiyum Pinne Njanum", he won the special jury award at the national and the state level.