His diplomatic triumph began when he entered Edo (now Tokyo) in November 1857 after receiving an invitation from the court of the 13th Tokugawa Shogun, Tokugawa Iesada (1824-1858), to negotiate the Treaty of Amity and Commerce Between the United States and Japan. This was Japans first treaty signed with a Western nation, on July 29, 1858, and subsequently ratified by the United States Senate on December 13, 1858. Townsend Harris is credited as the diplomat who first opened the Japanese Empire to foreign trade and culture.

After the treaty was signed by the Japanese officials, Harris moved his consulate to Edo. Following ratification by the Senate, Harris was promoted to Minister Resident by the State Department in 1859. Consulates were opened by European powers in Edo. However, the Treaty of Amity provoked a violent reaction from certain factions in Japan, and representatives of one of those factions attacked Henry Heuksen while he was returning from a party at the Prussian Embassy in January 1861, and he died shortly thereafter. Harris wrote about his thoughts in a letter addressed to Sir Rutherford Alcock (1809-1897), the British envoy in Japan, following the violent death of his secretary-interpreter. This incident gave the impetus for the European envoys to leave Edo and make calls for retaliatory action against the Japanese government. Harris alone refused to be stampeded and remarked:

I had hoped that the pages of future history might record the great fact that in one spot in the Eastern world the advent of Christian civilization did not bring with it its usual attendants of rapine and bloodshed; this fond hope, I fear, is to be disappointed.

I would sooner see all the Treaties with this country torn up, and Japan return to its old state of isolation, than witness the horrors of war inflicted on this peaceful people and happy land.

Townsend's courage in the face of this incident averted international tragedy and served as an example to the other envoys who sheepishly returned within a month to rejoin the most senior member of the diplomatic corps in Japan.