Canby was born in Piatt's Landing, Kentucky, to Israel T. and Elizabeth (Piatt) Canby. He attended Wabash College, but transferred to the United States Military Academy, from which he graduated in 1839. He was commissioned a second lieutenant in the 2nd U.S. Infantry and served as the regimental adjutant. Although often referred to as Edward Canby, a biographer has suggested that he was known as "Richard" during childhood and to some friends for most of his life.

In August 1872, Canby was posted to command the Pacific Northwest. He soon faced problems with the Modoc tribe, who had traditionally lived in Northern California. Forced to remove to a reservation in Oregon which they had to share with their traditional enemies, the Klamath tribe, they had pleaded with the US government to return to California. When the US refused, the Modoc left the reservation and returned illegally. In 1872, the US Army went to fight against them to force them back and the Modoc War broke out. The Modoc, entrenched in Captain Jack's Stronghold south of Tule Lake, resisted army attacks and fought US forces to a stalemate.  General Canby had received conflicting orders from Washington as to whether to make peace or war on the Modoc. As war was not working, the US government authorized a peace commission and assigned Canby a key position on it. There were many lines of communication between the Modoc and whites. At one point, someone told the Modoc leader Captain Jack that the governor of Oregon intended to hang nine Modoc, apparently without trial, as soon as they surrendered. The Modoc broke off scheduled talks; Canby was angered by the rumors and their action, as he believed that his federal authority trumped the governor's and made the threat irrelevant. Canby had no intention of allowing the Modoc to be punished without a trial.  On April 11, 1873, after months of false starts and aborted meetings, Canby went to another parley, unarmed and with some hope of final resolution. Judge Elijah Steele of Yreka, California wrote later that when he warned Canby that the Modoc were volatile and he was at risk, Canby replied, "I believe you are right, Mr. Steele, and I shall regard your advice, but it would not be very well for the general in command to be afraid to go where the peace commissioners would venture." The peace talks were held midway between the army encampment and Captain Jack's stronghold near Tule Lake. It was discovered later that two members of Canby's party brought concealed weapons and Modoc warriors were also armed.  According to Jeff C. Riddle, the Modoc son of the US interpreter and the author of Indian History of the Modoc War (1914), the Modoc had plotted before the meeting to kill Canby and the other commissioners, as they believed peace was not possible. They were determined to "fight until we die." (He was the son of Winema and Frank Riddle.) Captain Jack had been reluctant to agree to the killings, believing it "coward's work", but was pressured by other warriors to agree. He insisted on being given another chance to ask Canby to "give us a home in our country." When Canby said he did not have the authority to make such a promise, Captain Jack attacked the general. With Ellen's Man, one of his lieutenants, he shot Canby twice in the head and cut his throat. The Modoc also killed Reverend Eleazar Thomas, a peace commissioner, and wounded others in the party. Canby was the only general to be killed during the Indian Wars.

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