McLane was first elected to the U.S. House of Representatives by defeating Thomas Clayton for the Federalist nomination, as Clayton was politically damaged by having voted for a Congressional pay raise in the previous session. From then on the Clayton cousins became McLane's principle political opponents in Delaware. Nevertheless, McLane was elected six times as a Federalist to the U.S. House of Representatives, from 1816 through 1826. He had a most distinguished career in the U.S. House, serving five full terms from March 4, 1817 to March 3, 1827. In spite being a Federalist, he was Chairman of the Ways and Means Committee and it was only his Federalist affiliation that prevented him from being elected Speaker.