After leaving home, he worked as a grocer and pork packer in Clinton, Indiana, making trips via flatboat to sell produce along the Mississippi.

Dole faced heavy political backlash following the 1864 Sand Creek massacre, with many attributing corruption and incompetence with the office to his leadership.

Following the assassination of Abraham Lincoln, President Andrew Johnson considered Dole a political liability, and replaced him as commissioner with Dennis N. Cooley.

He was known for his humor as a politician; when Governor James Whitcomb made a speech calling on legislators to do what God would want done, Dole responded with a motion to send the matter to the clergy for further action.

Dole received a number of letters of recommendation from Indiana and Illinois politicians, leading Lincoln to send his nomination to the Senate on March 8, 1861.

He did not see combat during his service in the Black Hawk War, and lived in a region with very few remaining Native Americans, who were depopulated due to colonization and white settlement.

During his debates with Stephen Douglas, Lincoln stated that the basic rights outlined in the declaration of Independence applied to Black and Native American peoples.

"[12] Full land title to the allotments was only occasionally extended under Dole's administration, reserved to natives "sufficiently intelligent and prudent to control their affairs and interests".

[13] Dole believed that such polices would be pursued with the future goal of the termination of the reservations, suspending the federal government's administration of the tribes and incorporating natives as full citizens.

[14] By beginning widespread negotiation of treaties with western tribes and the shifting of priorities towards welfare programs in lieu of the prior focus on securing colonial land claims, he was able to forestall a major conflict while the American military was preoccupied during the early phases of the Civil War.

Opponents justified an absence of treaty rights in the Mexican Cession through a corresponding lack of recognition from the Spanish Empire during its colonization of the region.

[16] Dole's attempts to negotiate treaties and implement congressional appropriations to native tribes were blocked by regional military commanders during the later period of his time in office.

Generals such as Grenville M. Dodge and James Henry Carleton rejected Dole's efforts to negotiate with hostile tribes, considering only military force sufficient to impose submission to federal control.

[17] The newly appointed Secretary of the Interior James Harlan was particularly hostile to Dole, characterizing the Office of Indian Affairs as a "pack of thieves".