This study aims to discuss the continuity established between Machiavelli's political thoughts and the doctrine of the reason of state. Machiavelli's political doctrine, which tends to grasp actual power relations without reference to elements of theological and transcendental legitimacy, makes him the founder of modern politics. The autonomy of politics brings human activity to the center of the politics. According to the traditional interpretation, Machiavelli's emphasis on the artificial partnership of politics with his ethical-political views constitutes the classical formulation of the theory of reason of state. The holistic reduction of the post-death doctrine of the thinker to the concept of Machiavellianism reinforces this understanding. However, the primary forms of the reason of state, which mean the denial of the moral and religious against politics, do not coincide with this theoretical ground. Botero, who conceptualized the theory of the reason of state, put forward the opposite perspective with Machiavelli's teachings in the 16th century. Unlike Machiavelli, Botero problematizes the autonomy of politics against morality and religion and tries to make them compatible with each other. In this direction, our study aims to evaluate the post-Machiavelli problematics of the reason of state theory in the 16th century. Secondly, in this study Machiavelli's understanding of the state will be discussed with the Machiavellian principle and the theory of reason of state. The unfolding of these two lines of discussion will allow us to point out the levels of Machiavelli's interest in the theory of the reason of state in his political doctrine and in his time.