He is noted as a close friend of fellow philosopher John Locke, and for proposing Molyneux's Problem, a thought experiment widely discussed.

He was appointed Joint Surveyor General of the King's buildings and works in Ireland in 1684, serving alongside William Robinson.

In 1687 he invented a new type of sundial called a Sciothericum telescopicum that used a special double gnomon and a telescope to measure the time of noon to within 15 seconds.

His first book was editing and translating into English the work of René Descartes which was published in London, 1680 as Six Metaphysical Meditations, Wherein it is Proved that there is a God....

[7] Perhaps his best known scientific work was Dioptrica Nova, A treatise of dioptricks in two parts, wherein the various effects and appearances of spherick glasses, both convex and concave, single and combined, in telescopes and microscopes, together with their usefulness in many concerns of humane life, are explained, published in London 1692.

This controversial[5] work—through application of historical and legal precedent—dealt with contentious constitutional issues that had emerged in the latter years of the seventeenth century as a result of attempts on the part of the English Parliament to pass laws that would suppress the Irish woollen trade.

Molyneux's arguments reflected those made in an unpublished piece written about 1660 by his father-in-law Sir William Domville, entitled A Disquisition Touching That Great Question Whether an Act of Parliament Made in England Shall Bind the Kingdom and People of Ireland Without Their Allowance and Acceptance of Such Act in the Kingdom of Ireland.

Molyneux died in Dublin on 11 October 1698 and was buried in St. Audoen's Church, within the burial vault of his great-grandfather, Sir William Ussher.