He received higher education from St. Mary's College in Baltimore, Maryland until he moved with his family to Europe, after his father had been appointed as an ambassador to England.

In 1845, McLane was elected as a representative of Baltimore City to the Maryland House of Delegates after successfully campaigning for President James K. Polk a year previous.

After his tenure in Congress, McLane moved to the Western United States to become a counsel for a mining corporation, which was engaged in legal activities regarding property in California.

After his return to the United States, he resumed his political activity by serving as delegate to the Democratic National Convention in 1856, during which he supported future President James Buchanan.

McLane was appointed Envoy Extraordinary and Minister Plenipotentiary to Mexico on March 7, 1859, and was charged to determine if the government of Benito Juárez was worthy of recognition.

He also negotiated, as ambassador, the McLane-Ocampo Treaty, which would have expanded the transit rights of the U.S. across the Isthmus of Tehuantepec to include an interoceanic canal concession.

During the American Civil War, the federal government, under President Abraham Lincoln, forcibly forbade the state of Maryland from joining the Confederacy.

During the rest of the war, McLane refocused his attention back towards his law practice, as he had been appointed counsel for the Western Pacific Railroad in the winter of 1863.

McLane would continue to devote his energies towards his law practice until well after the end of the Civil War and did not re-enter politics until the Democratic National Convention in 1876.

McLane only served as governor for slightly over a year, from January 8, 1884, until his resignation on March 27, 1885, having been appointed by President Grover Cleveland as United States Minister Plenipotentiary to France.