In 1758, Helvétius published his philosophical magnum opus, a work called De l'esprit (On Mind). Its atheistic, utilitarian and egalitarian doctrines raised a public outcry and Helvétius was forced to issue several retractions.

After ten years, when he thought his fortune sufficient, he gave up the post of farmer general, and retired to a country estate, where he employed his fortune in the relief of the poor, the encouragement of agriculture and the development of industries. For this he won the admiration of many of the philosophers.

In 1764, Helvétius visited England, and the next year, at the invitation of Frederick II, went to Berlin, where the king paid him much attention. He then returned to his country estate and passed the remainder of his life peacefully.

Helvétius' philosophical studies ended in the production of his famous book De l'esprit (On Mind). It was first published in 1758 and was intended to be the rival of Montesquieu's Spirit of the Laws, with Helvétius arguing strongly against Montesquieu's theory that climate influenced the character of nations. The work attracted immediate attention and aroused the most formidable opposition, especially from the Dauphin Louis, son of King Louis XV. The Sorbonne condemned the book, while the priests persuaded the court that it was full of the most dangerous doctrines. The book was declared to be heretical – so atheistic that it was condemned by Church and State and was burned. Helvétius, terrified at the storm he had raised, wrote three separate and humiliating retractions. In spite of his protestations of orthodoxy, the book was publicly burned by the Paris hangman.

It had incredibly negative effects on the rest of the philosophes, in particular, Denis Diderot, and the great work he was doing on the Encyclopedie. The religious authorities, particularly the Jesuits and the new Pope began to fear the spread of atheism and wanted to clamp down on the 'modern thought' hard and quickly. 'De l'Espirit' became almost a scapegoat for this.

This great publicity resulted in the book being translated into almost all the languages of Europe. Voltaire said that it lacked originality. Rousseau declared that the very benevolence of the author gave the lie to his principles.Grimm thought that all the ideas in the book were borrowed from Diderot. Madame du Deffand felt that Helvétius had raised such a storm by saying openly what every one thought in secret. Madame de Graffigny claimed that all the good things in the book had been picked up in her own salon.

Helvétius' philosophy belongs to the utilitarian school:

1. All man's faculties may be reduced to physical sensation, even memory, comparison, judgment. Our only difference from the lower animals lies in our external organization.
2. Self-interest, founded on the love of pleasure and the fear of pain, is the sole spring of judgment, action, and affection. Human beings are motivated solely by the pursuit of pleasure and the avoidance of pain. "These two," he says, "are, and always will be, the only principles of action in man." Self-sacrifice is prompted by the fact that the sensation of pleasure outweighs the accompanying pain and is thus the result of deliberate calculation.
3. We have no freedom of choice between good and evil. There is no such thing as absolute right – ideas of justice and injustice change according to customs.

This view of man was largely Hobbesian – man is a system deterministically controllable by a suitable combination of reward and punishment, and the ends of government are to ensure the maximisation of pleasure.

"All men," Helvétius maintained, "have an equal disposition for understanding.". As one of the French Enlightenment's many Lockean disciples, he regarded the human mind as a blank slate, but free not only from innate ideas but also from innate natural dispositions and propensities. Physiological constitution was at most a peripheral factor in men's characters or capabilities. Any apparent inequalities were independent of natural organization, and had their cause in the unequal desire for instruction. This desire springs from passions, of which all men commonly well organized are susceptible to the same degree. We thus owe everything to education. Social engineering is therefore an enterprise unconstrained by the natural abilities of men. This natural equality applied to all men in all nations, and thus the differences in national characteristics were not the result of innate differences between the people therein, but rather a byproduct of the system education and government. "No nation," wrote Helvétius, "has reason to regard itself superior to others by virtue of its innate endowment." This radically egalitarian aspect of Helvétius' philosophy caused Diderot to remark that if it were true, De l'esprit might just as well have been written by Helvétius' dogkeeper.

Since all men have the same natural potential, Helvétius argued, they all have the same ability to learn. Thus, education is the method by which to reform society, and there are few limits to the drastic social improvements that could be brought about by the appropriate distribution of education. Although people seem to possess certain qualities in greater abundance than their neighbours, the explanation for this comes 'from above' – it is caused by education, law and government. "If we commonly meet in London, with knowing men, who are with much more difficulty found in France," this is because it is a country where "every citizen has a share in the management of affairs in general." "The art of forming men," he concludes, "is in all countries [...] strictly connected to the form of the government", and thus education via governmental intervention is the method of reform.

The crux of his thought was that public ethics has a utilitarian basis, and he insisted strongly on the importance of culture and education in national development. His thinking can be described as unsystematic. The original ideas in his system are those of the natural equality of intelligences and the omnipotence of education, neither of which gained general acceptance, though both were prominent in the system of John Stuart Mill. Cesare Beccaria states that he was largely inspired by Helvétius in his attempt to modify penal laws. Helvétius also exerted some influence on the utilitarian Jeremy Bentham.

The materialistic aspects of Helvétius, along with Baron d'Holbach, had an influence on Karl Marx, the theorist of historical materialism. Marx, the theorist behind communist ideologies of the 20th century, studied the ideas of Helvétius in Paris and later called the materialism of Helvétius and d'Holbach "the social basis of communism".

His poetic ambitions resulted in the poem called Le Bonheur (published posthumously, with an account of Helvétius's life and works, by Jean François de Saint-Lambert, 1773), in which he develops the idea that true happiness is only to be found in making the interest of one person that of all.

British philosopher Isaiah Berlin listed Helvetius, along with Hegel, Fichte, Rousseau, Saint-Simon and Maistre as one of the six "enemies of freedom" who constituted the ideological basis for modern authoritarianism, in his book Freedom and Betrayal: Six Enemies of Human Liberty.