After Moore's withdrawal, Hopkins partnered with three of his brothers and established "Hopkins & Brothers Wholesalers" in 1819. The company prospered by selling various wares in the Shenandoah Valley from Conestoga wagons, sometimes in exchange for corn whiskey, which was then sold in Baltimore as "Hopkins' Best". The bulk of Hopkins' fortune however was made by his judicious investments in myriad ventures, most notably the Baltimore and Ohio Railroad (B&O), of which he became a director in 1847 and chairman of the Finance Committee in 1855. He was also President of Merchants' Bank as well as director of a number of other organizations. After a successful career, Hopkins was able to retire at the age of 52 in 1847.