D'Holbach had one of the more notable salons in Paris. It was one of the most important meeting places for contributors to the Encyclopédie. Meetings were held regularly twice a week from approximately 1750 - 1780. The tone of discussion among the visitors was highly civilized and it covered more diverse topics than that of other salons. This, along with other features including excellent food, expensive wine, and a library of over 3000 volumes, attracted many notable visitors.

Among the regulars in attendance at the salon were: Diderot, Grimm, Jean-François Marmontel, D'Alembert, Helvétius, Ferdinando Galiani, and André Morellet. The salon was also well-frequented by British intellectuals: Adam Smith, David Hume, Horace Walpole, Edward Gibbon, amongst others. D'Holbach was owner of Heeze Castle, situated in the Duchy of Brabant, actually in the Netherlands.

For the Encyclopédie he authored and translated a large number of articles on topics such as politics, religion, chemistry and mineralogy. The translations he contributed were chiefly from German sources. He was better known, however, for his philosophical writings. These writings expressed a materialistic and atheistic position. His work is today categorised into the philosophical movement called "French materialism".

In 1767 Christianity unveiled (Christianisme dévoilé) appeared, in which he attacked Christianity and religion as counter to the moral advancement of humanity. This was followed up by other works, and in 1770 by a still more open attack in his most famous book, The System of Nature (Le Système de la nature).

Denying the existence of a deity, and refusing to admit as evidence all a priori arguments, d'Holbach saw in the universe nothing save matter in motion. In this, he was influenced by John Toland. The foundation of morality is happiness: "It would be useless and almost unjust to insist upon a man's being virtuous if he cannot be so without being unhappy. So long as vice renders him happy, he should love vice." This theory of morality can be seen as a precursor to utilitarianism.

Le Système de la nature presented a core of radical ideas which many contemporaries found disturbing, thus prompting a strong reaction. The Catholic Church in France threatened the crown with a withdrawal of financial support unless it effectively suppressed the circulation of the book. The list of people writing refutations of the work was long. The Roman Catholic Church had its pre-eminent theologian Nicolas-Sylvestre Bergier write a refutation of the Système titled Examen du matérialisme (Materialism examined).

Voltaire hastily seized his pen to refute the philosophy of the Système in the article "Dieu" in his Dictionnaire philosophique, while Frederick the Great also drew up an answer to it. Its principles are summed up in a more popular form in Bon Sens, on idées naturelles opposees aux idées surnaturelles (Amsterdam, 1772), In the Système social (1773), the Politique naturelle (1773-1774) and the Morale universelle (1776) Holbach attempts to describe a system of morality in place of the one he had so fiercely attacked, but these later writings were not as popular or influential as his earlier work.

Due to a fear of persecution, he published his books either anonymously or under pseudonyms. Additionally, the books were published outside of France, usually in Amsterdam. D'Holbach was strongly critical of abuses of power in France and abroad. Contrary to the revolutionary spirit of the time however, he called for the educated classes to reform the corrupt system of government and warned against revolution, democracy, and "mob rule".

It is thought that the virtuous atheist Wolmar in Jean-Jacques Rousseau's Julie, ou la nouvelle Héloïse is based on d'Holbach. Many of the main points in d'Holbach's philosophy have now found increasing resonance among the scientifically literate.