Inspired by the social and political movements of the 1960s, Mankiller became involved in the Occupation of Alcatraz and later participated in the land and compensation struggles with the Pit River Tribe.

With her expertise at preparing documentation, she became a successful grant writer, and by the early 1980s was directing the newly created Community Development Department of the Cherokee Nation.

As Director she designed and supervised innovative community projects allowing rural citizens to identify their own challenges and, through their labor, participate in solving them.

She developed revenue streams, including factories, retail stores, restaurants and bingo operations, while establishing self-governance, allowing the tribe to manage its own finances.

[37][38] That summer, at a Latin dance, she met Hector Hugo Olaya de Bardi, an Ecuadorian college student from a well-to-do family, and the two began dating.

While Olaya continued with his schooling at San Francisco State University and worked for Pan American Airlines, Mankiller was busy raising their daughters.

In October 1969, the Center burned, and the loss of their meeting place created a bond between administrators and student activists, who combined their efforts to bring the plight of urban Native Americans to the public eye with the reoccupation of Alcatraz.

[52] Against her husband's wishes, she bought her own car and began to seek independence, taking her daughters to Native American events along the West Coast.

[54][55][56] Over the next five years, she assisted the tribe in raising funds for its legal defense and helped prepare documentation for their claim, gaining experience in international and treaty law.

Taking a position as a social worker with the Urban Indian Resource Center, she worked on programs conducting research on child abuse and neglect,[59] foster care, and adoption of Native children.

[62][66] That same year she enrolled in additional classes at Flaming Rainbow University in Stilwell, Oklahoma, completing her Bachelor of Science degree in social sciences with an emphasis on Indian Affairs, thanks to a correspondence course under a program offered by the Union for Experimental Colleges in Washington, D.C.[67][68][69] She enrolled in graduate courses in community development at the University of Arkansas, in Fayetteville,[70][71] while continuing to work in the tribal offices as an economic stimulus coordinator.

By the time Mankiller was elected deputy, the mixed-blood faction focused on economic growth and favored non-Natives being hired to run Native businesses if they were more qualified.

[116][117] In articles such as a November 1985 interview in People, Mankiller strove to show that Native cultural traditions of cooperation and respect for the environment made them role models for the rest of society.

[116] Because she lacked favor with the Tribal Council, she also used her access with the press to educate Cherokee voters on the goals of her administration and her desire to improve housing and health services.

She established employment training opportunities and programs that offered financial and technical expertise to tribal members who wanted to start their own small enterprises.

Thinking that it was going to be a productive meeting, Mankiller, who had been chosen as one of the three spokespeople for the 16 invited chiefs, was disappointed that Reagan discounted their issues and merely reiterated his pledge for self-determination.

The compact, signed by Governor David Walters and leadership of all of the Five Civilized Tribes except the Muscogee (Creek) Nation, allowed the chiefs to collect state taxes and retain a portion of the revenues.

[90][138] While she was in Boston recuperating from the transplant, she met with officials from Washington, D.C., and signed an agreement for the Cherokee Nation to participate in a project that allowed the tribe to self-govern and assume responsibility for the use of federal funds.

Hearings on the matter resulted in amendments in 1988 to the Indian Self-Determination and Education Assistance Act of 1975, to allow ten tribes to participate in a pilot program spanning five years.

Similarly, she opposed legislation proposed by the Oklahoma House of Representatives to collect cigarette taxes on products sold at Indian smoke shops to non-Indians.

[131] In the continuing battle over compensation for the loss of access to mineral rights owned by the tribe in the Arkansas River, Mankiller estimated that one-third of her time as chief was spent on trying to obtain a settlement.

Mankiller worked with tribal registrar Lee Fleming and a staff member Richard Allen to document groups which claimed Cherokee heritage, and they compiled a list of 269 associations throughout the country.

Together, it teaches us that, as long as people like Wilma Mankiller carry the flame within them, centuries of ignorance and genocide can't extinguish the human spirit".

[169] That same year, Mankiller was invited by Clinton to moderate the Nation-to-Nation Summit, in which leaders of all 545 federally recognized tribes in the United States were assembled to discuss a variety of topics.

[177] Byrd's administration became embroiled in a constitutional crisis, which he blamed on Mankiller, stating that her failure to attend his inauguration and lack of mentoring divided the tribe and left him without experienced advisors.

[180] Despite calls from the US Secretary of the Interior, Bruce Babbitt, for congressional intervention and Oklahoma Senator Jim Inhofe's desire for presidential action, Mankiller continued to maintain that the problem was one of inexperienced leadership, in which she did not want to be involved.

[181] When an independent group of legal analysts, known as the "Massad Commission", was assembled in 1997 to evaluate the problems in Byrd's administration, Mankiller, in spite of her ongoing health concerns, was called to testify.

[206] Over the course of her three terms as Principal Chief, Mankiller reinvigorated the Cherokee Nation through community development projects where men and women work collectively for the common good.

[209] A 2013 feature film, The Cherokee Word for Water, tells the story of the Bell waterline project that helped launch Mankiller's political career and started her friendship with her future husband, Charlie Soap.

[215] In 2021, it was announced that Mankiller, Maya Angelou, Sally Ride, Adelina Otero-Warren and Anna May Wong were each selected to have their likeness appear on a quarter-dollar coin[216] as a part of the United States Mint's "American Women quarters" Program.