Retained in the navy reduction of 1801, Biddle served in the war against the Barbary pirates. The ship he was in, USS Philadelphia, struck rocks off Tripoli, and along with his Commodore, William Bainbridge, he was kept imprisoned by the pirates for 19 months.
During the War of 1812, Biddle was first lieutenant in USS Wasp. After this, he was in command of the sloop USS Hornet when she defeated HMS Penguin. Later, in 1817, he was sent to the Columbia River to formally take over the Oregon Country for the United States, which was completed in 1818.
After the war, Biddle performed various duties in the Gulf of Mexico, the South Atlantic and the Mediterranean. In 1830, Biddle and US consul David Offly negotiated and concluded a treaty with the Sublime Porte. The treaty was later used by US diplomats to claim extraterritorial privileges for US citizens in the Ottoman Empire.
On July 20 1846, he anchored with the two warships USS Columbus and USS Vincennes in Uraga Channel at the mouth to Tokyo Bay in an attempt to open up Japan to trade with the United States, but was ultimately unsuccessful. Biddle delivered his request that Japan agree to a similar treaty to that which he had just negotiated with China. A few days later a Japanese junk approached Biddle's flagship and requested his presence on board their ship to receive the Tokugawa shogunate's official response. Biddle at first demurred but eventually agreed. As Biddle attempted to board the Japanese ship he misunderstood the instructions of one of the samurai guards and was physically knocked back by the guard who then drew his sword. Biddle retreated to his flagship. The Japanese officials apologized for the mishap. Biddle eventually received the shogunate's response and was told that Japan forbade all commerce and communication with foreign nations besides that of the Dutch; also, he was informed that all foreign affairs were conducted through Nagasaki and that his ships should leave Uraga immediately.
Seven years later, Commodore Matthew Perry did the task with four warships. Perry was well aware of Biddle's reception and strove to make sure that he would not be treated in the same manner.
Biddle died in Philadelphia and is buried at Christ Church Burial Ground in the family plot.