During an attack of fever he made observations on himself with reference to the action of quickened circulation upon thought, which led him to the conclusion that psychical phenomena were to be accounted for as the effects of organic changes in the brain and nervous system. This conclusion he worked out in his earliest philosophical work, the Histoire naturelle de l'âme (1745). So great was the outcry caused by its publication that La Mettrie was forced to take refuge in Leiden, where he developed his doctrines still more boldly and completely, and with great originality, in L'Homme machine (Eng. trans., London, 1750; ed. with introd. and notes, J. Asszat, 1865), and L'Homme plante, treatises based upon principles of the most consistently materialistic character.

The ethics of these principles were worked out in Discours sur le bonheur, La Volupté, and L'Art de jouir, in which the end of life is found in the pleasures of the senses, and virtue is reduced to self-love. Atheism is the only means of ensuring the happiness of the world, which has been rendered impossible by the wars brought about by theologians, under the excuse of an inexistent "soul". When death comes, the farce is over (la farce est jouée), therefore let us take our pleasure while we can.

La Mettrie has been called the Aristippus of modern materialism. So strong was the feeling against him that in 1748 he was compelled to quit the Netherlands for Berlin, where Frederick the Great not only allowed him to practise as a physician, but appointed him court reader. There La Mettrie wrote his major book "Discours sur le bonheur" (1748), which caused the "ban" by leading enlightenment thinkers as Voltaire, Diderot, D'Holbach. His collected Oeuvres philosophiques appeared after his death in several editions, published in London, Berlin and Amsterdam respectively.

La Mettrie's celebration of sensual pleasure was said to have resulted in his early death. Those who disagreed with La Mettrie's philosophy used his death to claim that atheistic sensuality justifiably results in an untimely demise.

The French ambassador Tirconnel was very grateful to La Mettrie for curing him of an illness. A feast was given to celebrate the recovery. It is claimed that La Mettrie wanted to show either his power of gluttony or his strong constitution by devouring a large quantity of pâte aux truffes. As a result, he developed a fever, became delirious, and died.

Frederick the Great gave the funeral oration. He declared, "La Mettrie died in the house of Milord Tirconnel, the French plenipotentiary, whom he had restored to life. It seems that the disease, knowing with whom it had to deal, was cunning enough to attack him first by the brain, in order to destroy him the more surely. A violent fever with fierce delirium came on. The invalid was obliged to have recourse to the science of his colleagues, but he failed to find the succor that his own skill had so often afforded as well to himself as to the public."

However, in a confidential letter to the Markgräfin von Bayreuth, Frederick wrote," He was merry, a good devil, a good doctor, and a very bad author. By not reading his books, one can be very content." He then mentioned that La Mettrie had indigestion from the pheasant paste. The actual cause of his death, however, was the bloodletting that La Mettrie had prescribed for himself. Frederick asserted that the German doctors did not condone bleeding a patient, and La Mettrie was trying to prove them wrong.