Mistahimaskwa was born around 1825 near Jackfish Lake, north of present-day North Battleford. His father, Black Powder, an Ojibwa, was the Chief of a small mixed band of Cree and Ojibwa and his mother was a member of one of these nations.
Mistahimaskwa began establishing himself as a leader in the late 1850s and early 1860s. In 1871 he was the leading chief of the Prairie River People and by 1874, headed a camp of 65 lodges (approximately 520 people). His influence rose steadily in the following years, reaching its height in the late 1870s and early 1880s.
Although he appeared at the negotiations, Mistahimaskwa refused to sign Treaty No. Six: he was the first major chief on the prairies to do so. Over the next six years, Mistahimaskwa continued to refuse treaty. Finally on 8 December 1882, faced with destitution and starvation, Mistahimaskwa signed an adhesion to the treaty. At this time his following had dwindled to 114 people.
In the late 1870s Mistahimaskwa tried to create a political confederation of Indian bands capable of forcing concessions from the government. From 1878 to 1880 he traveled through the Canadian North-West and Montana trying to unite the bands. In the 1880s Mistahimaskwa's efforts focused on uniting Cree bands and attempting to create an Indian territory in the Northwest through adjacent reserves. The government refused to grant contiguous reserves and and did not respond to joint gatherings of Cree bands, such as the one organized by Mistahimaskwa at Fort Battleford in May 1884 to present Indian grievances. In June 1884, Mistahimaskwa hosted a Thirst Dance at the Poundmaker Reserve. The event, which was attended by over 2000 people, was disrupted by the NWMP and only the efforts of Mistahimaskwa and Pitikwahanapiwiyin (Poundmaker) averted violence.
As a result of the government's refusal to negotiate with him, Mistahimaskwa began to lose influence over the band's warrior society during the winter of 1884-1885. On 2 April 1885, Mistahimaskwa's band led by his son Ayimisis and the war chief, Kapapamahchakwew (Wandering Spirit), killed nine people at Frog Lake. Mistahimaskwa's efforts to stop the massacre failed. No longer in control of the band, Mistahimaskwa remained in the background counseling peace during the rest of the resistance. On 14 April Kapapamahchakwew moved to attack Fort Pitt. Mistahimaskwa successfully negotiated the surrender of the fort's 44 civilian inhabitants and the police evacuation. The band fought General Strange at Frenchman's Butte on 28 March, and again at Loon Lake on 3 June. Mistahimaskwa did not participate in the fighting on either occasion.
Mistahimaskwa surrendered at Fort Carlton on 2 July. He was brought to trial in Regina on 11 September. After deliberating for fifteen minutes, the jury found him guilty of treason-felony, and he was sentenced to three years at the Stony Mountain Penitentiary. Released in February 1887 because of poor health, Mistahimaskwa settled on the Poundmaker reserve where he died on 17 January 1888.