In 1867, Minor co-founded and became the first president of the Woman's Suffrage Association of Missouri (later an affiliate of the American Woman Suffrage Association). Minor personally sided with the National Woman's Suffrage Association, prompting her resignation as President of the Missouri Association. At an 1869 convention in St. Louis, Minor stated that "the Constitution of the United States gives me every right and privilege to which every other citizen is entitled." Later that year, Francis and Virginia Minor drafted and circulated pamphlets arguing for women's suffrage based on the newly passed Fourteenth Amendment.
On October 15, 1872, Virginia Minor attempted to register to vote in St. Louis. When election registrar Reese Happersett turned her down, Virginia (represented by Francis) filed suit in the Missouri state courts. The trial court, Missouri Supreme Court, and United States Supreme Court all ruled in favor of the state of Missouri. The Supreme Court unanimously held "that the Constitution of the United States does not confer the right of suffrage upon any one", and that the decision of who should be entitled to vote was left to the legislative branch.
Virginia Minor testified in support of women's suffrage before the United States Senate in 1889, and was honorary vice president of the Interstate Woman Suffrage Convention in 1892. She died in St. Louis in 1894 and is buried at Bellefontaine Cemetery.