Born in Asheville, North Carolina on March 9, 1922, McKissick did his undergraduate work at Morehouse and North Caroline colleges, and later graduated form the University of North Caroline Law School.

During World War II McKissick served in the European Theater as a sergeant. After the war, he began legal practice in Durham, North Caroline, where he once represented his own daughter in her successful bid to gain admission to a previously all-white public school.

Despite the victory, McKissick later decided that "integration" itself only magnified the perils faced by many black children, McKissick bitterly recalled that his children had been taunted and harassed: "Patches cut out of their hair, pages torn out of books, water thrown on them in the dead of winter, ink down the front of their dresses"-a demoralizing array of constant and relentless pressures designed to crack their composure and destroy their will to learn. The adversity no doubt deepened McKissick’s nascent radicalism and militant zeal.

As a lawyer, McKissick’s most publicized efforts involved a segregated black local in the Tobacco Workers International, an AFL-CIO member. McKissick pressed to have black workers admitted to the skilled scale without loss of their seniority rating. McKissick also successfully defended "sit-in" protestors in the South.

It was at this time the rupture widened between the older, established civil rights groups, dependent for their programming on a coalition of educated blacks and affluent whites liberals, and the younger, more rancorous black militants who turned their backs on most institutional whites support. The militants argued that the civil rights groups did not appreciate the urgency of many problems affecting black urban majorities, particularly in the job area where technology often reduced people to ciphers.

When Floyd McKissick replaced James Farmer as head of CORE on January 3, 1966, the organization completed a 180-degree turn that saw it change from an interracial integrationist civil rights agency pledged to uphold nonviolence into a militant and uncompromising advocate of the ideology of black power. McKissick and Roy Innis, who at that time was the head of the Harlem chapter of CORE, were close allies, and when McKissick left CORE in 1968, Innis took over.

After leaving CORE, McKissick launched a plan to build a new community, Soul City, on Warren County North Carolina farmland. McKissick saw Soul City as an integrated community with sufficient industry to support a population of 55,000. For his venture, he received a $14 million bond issue guarantee from the Department of Housing and Urban Development and a loan of $500,000 form the First Pennsylvania Bank.

Soul City, however, ran into difficulties and despite the best offers of McKissick, the project never developed as he had anticipated. Finally, in June 1980, the Soul City Corporation and the federal government reached an agreement that would allow the government to assume control the following January. Under the agreement, the company retained 88 acres of the project, including the site of a mobile home park and a 60,000 square foot building that had served as the project’s headquarters.

The Department of Housing & Urban Development paid off $10 million in loans and agreed to pay an additional $175,000 of the project’s debts.  In exchange, McKissick agreed to drop a lawsuit brought to block HUD from shutting down the project.