During his days in Dravida Kazhagam, Annadurai had supported Periyar's call for an independent Dravida Nadu. The claim for such an independent state stayed alive in the initial days of DMK. E. V. K. Sampath, who had earlier forfeited his inheritance from Periyar to join DMK, saw the call for Dravida Nadu as an unrealistic goal. Responding to Sampath's concern, Annadurai said 

Sampath's opposition to using film stars made him cross swords with many other members of the party. Eventually, with looming differences with Annadurai and other leaders on Dravida Nadu, Sampath left the DMK and formed his own party, the Tamil Nationalist Party, in 1961. In 1962, Annadurai said in the Rajya Sabha that "Dravidians want the right of self-determination ... We want a separate country for southern India".

However, the reorganisation of states in India on linguistic basis removed Kannada, Telugu and Malayalam speaking regions from the Madras Presidency leaving behind a predominantly Tamil Madras State. Giving in to realities, Annadurai and his DMK changed the call of independent "Dravida Nadu for Dravidians" to independent "Tamil Nadu for Tamils". Annadurai felt that remaining in the Indian Union meant accepting linguistic domination and economic backwardness. Nevertheless, the Sino-Indian war brought about changes in the Indian constitution. The Sixteenth Amendment (most popularly known as the "Anti-Secessionist Amendment") banned any party with sectarian principles from participating in elections. When this amendment was presented in the Parliament of India, Annadurai was one of its members. He vehemently debated against the amendment, but eventually could not stop it from being passed. Faced with the new constitutional changes, Annadurai and his DMK left the call for an independent Tamil homeland on the back burner.
From then on Annadurai and his DMK aimed at achieving better co-operation between the southern states and claimed more autonomy for Tamil Nadu.
On the party's position, Annadurai said 

మతం
1953లో నిరసనలు
ద్రవిడ నాడు
రాజకీయ ప్రవేశం