On his return to France in 1622, after successfully completing his service, he engaged himself in the study of the mind. It was here, that he published his very first paper called Regulae ad Directionem Ingenii (Rules for the Direction of the Mind). In 1628, he enrolled himself at the University of Franeker and the Leiden University in order to study mathematics, and later, moved to Netherlands. He stayed there for over 20 years, during which, he wrote and published various philosophical and mathematical works. In 1643, he began corresponding with Princess Elisabeth of Bohemia about moral and psychological topics. His subsequent manuscript Les Passions de l'âme (Passions of the Soul) was dedicated to the Princess. This text was later read by Christina, Queen of Sweden, who developed an interest in Descartes's ideas about love. This prompted her to invite Descartes to Stockholm in order to organize a new scientific academy, and also, to tutor her. Due to her busy and demanding schedule, the tutoring was scheduled early every morning. This coupled with the cold and drafty environment in the castle caused him to develop a cold, that steadily progressed into a serious respiratory infection. This eventually led to his untimely death on 11 February 1650, at the age of 53.

René Descartes never married. He did, however, have a brief affair with a servant named Helena Jans van der Strom, which resulted in the birth of his daughter, Francine. Unfortunately, she fell victim to scarlet fever in 1640 and passed away.

Descartes was the first to emphasize the use of reason to develop natural science. He expressed it as: "All Philosophy is like a tree, of which Metaphysics is the root, Physics the trunk, and all the other sciences the branches that grow out of this trunk, which are reduced to three principals, namely, Medicine, Mechanics, and Ethics. By the science of Morals, I understand the highest and most perfect which, presupposing an entire knowledge of the other sciences, is the last degree of wisdom." His most famous doctrine is known as cogito ergo sum (English: "I think, therefore I am"). It implied that if the existence of an object or being is questioned, then the very act of doubting proves that it exists. He defines "thought" (cogitatio) as "what happens in me such that I am immediately conscious of it, insofar as I am conscious of it". He explains that the faculty or ability to think, is the only indubitable source of knowledge as the senses that one uses to perceive the environment can be easily fooled. The fallibility of the senses is demonstrated by him using the example of wax. If one considers a piece of wax, the basic size, shape, texture, color, smell, and other such attributes can be ascertained by the use of our senses. But if the very same piece is, then, held next to a flame, these attributes change completely. The characteristics of this new form are distinct and dissimilar, even though the object (wax) is still the same. The gap between the different observations can solely be bridged by thinking, as it will allow the person to fully grasp and understand the nature of wax in order to reconcile the two different sets of characteristics with the same object. With this argument as the basis, he constructed a system that discards perceptive clues in favor of pure deductions in order to understand a concept or phenomenon. In his works, he suggested that the human body operates like a machine (it has material properties); whereas, the mind (or soul) is non-material that does not follow the laws of nature. He proposed that the mind generally controls the body, but sometimes the body can also influence the mind when people act out of passion. This dual direction of control was termed dualism. He believed that the cerebrospinal fluid of the ventricles acted via the nerves in order to control the body, and that this process was influenced by the pineal gland. Sensations received by the pineal gland caused it to vibrate, in turn giving rise to emotions, thereby, allowing the body to act and control the mind. Cartesian or analytic geometry, which uses algebra to describe geometry, was one of Descartes's most influential contributions. He formulated the convention of depicting unknown variables as x, y, and z, and known values as a, b, and c. He also put forth the notation system that utilizes superscripts to indicate powers or exponents. He was the first to propose algebra as a method of reasoning for abstract and unknown quantities. His work provided the base for the development of Calculus by Newton, which in turn, allowed Gottfried Leibniz to develop it further into a evolved form of modern mathematics. Descartes also discovered an early form of the law of conservation of mechanical momentum, and outlined his views on the Universe in his Principles of Philosophy. He also made contributions to the field of optics by proving that the angular radius of a rainbow is 42 degrees. He also independently discovered the law of reflection.