With his brothers Jeremiah and Thomas, he took over the lease of Anthony Bacon's cannon foundry at Cyfarthfa, before they began the Penydarren Ironworks during the 1780s.
In 1784, after a court case[1] they transferred the lease of the foundry from Anthony Bacon (with whom they had quarrelled), who reassigned it to David Tanner, and moved to where they had set up the works on the banks of the River Morlais, building Penydarren House on the far side river bank.
Samuel was one of the chief promoters of the Glamorgan canal, which opened in 1795 and cost £103,000, of which he subscribed £40,000 and which enabled the transporting of heavy manufactured iron to Cardiff docks.
In 1804, Samuel won a 1000 guineas wager with Richard Crawshay as to which of them could first build a steam locomotive for use in their works.
Homfray employed Richard Trevithick for this purpose and his locomotive won the bet, hauling five wagons, carrying ten tons of iron and seventy men, at a speed of five miles an hour.