Though reared a Calvinist, More became an Anglican as a youth. At Christ's College, Cambridge, he encountered such Platonists as Edward Fowler and John Worthington. In 1639 he was elected to a fellowship at Cambridge.

More gradually abandoned his admiration for the thought of the French philosopher René Descartes (Descartes, René), which separated mind and matter, and he came to hold that Cartesian philosophy must inevitably lead to some form of mechanical naturalism and to atheism. In their correspondence of 1648–49, published as The Immortality of the Soule (1659), and in his major metaphysical work, Enchiridion Metaphysicum (1671), More argued against Descartes's indentification of matter with extension. To deny that spirit exists in extension as well as thought, More maintained, was to reduce it to a nonentity that could exert no influence on the processes of the world. Not only individual minds but God must be extended: indeed, infinite space reveals certain of the attributes of deity. The latter concept may have influenced Sir Isaac Newton in his ideas about space. In a similar fashion, More sought to refute the claim of Thomas Hobbes that theism is impossible because the human mind cannot know an immaterial substance.

More's early poetry was written in a style akin to that of Edmund Spenser and treated metaphysical subjects. His religious views, most fully expressed in An Explanation of the Grand Mystery of Godliness (1660) and Divine Dialogues (1668), centred on his idea of reconciling Christian Platonism with 17th-century science. His ethical writings include Enchiridion Ethicum (1667); his work An Antidote against Atheism (1652) is curiously devoted, in large part, to witch and ghost stories. His poetry is published in Alexander Balloch Grosart's Complete Poems of Henry More (1878). Excerpts from his philosophical writings appear in Flora Isabel MacKinnon's Philosophical Writings of Henry More (1925).