Freeman performed 3,439 lobotomies, but more significantly he popularized the lobotomy as a legitimate form of psychosurgery. A neurologist and psychiatrist without surgical training, he initially worked with several surgeons, including James W. Watts. In 1936, he and Watts became the first American doctors to perform prefrontal lobotomy.

Frustrated by his lack of surgical training and seeking a faster and less invasive way to perform the procedure, Freeman invented the "ice pick" or transorbital lobotomy, which, at first, literally used an ice pick hammered through the back of the eye socket into the brain. Freeman was able to perform these very quickly, outside of an operating theatre, and without the assistance of an actual surgeon. For his first transorbital lobotomies, Freeman used an actual icepick from his kitchen. Later, he utilized an instrument created specifically for the operation called a leucotome[citation needed]. In 1948 Freeman developed a new technique which involved wrenching the leucotome in an upstroke after the initial insertion. This procedure placed great strain on the instrument and often resulted in the leucotome breaking off in the patient's skull. As a result, Freeman designed a new, stronger instrument, the orbitoclast.

Freeman embarked on a national campaign in his van which he called his "lobotomobile" to demonstrate the procedure to surgeons working at state-run institutions. According to some, institutional care was hampered by lack of effective treatments and extreme overcrowding, and Freeman saw the transorbital lobotomy as an expedient tool to get large populations out of treatment and back into private life.

Freeman's most notorious operation was on the ill-fated Rosemary Kennedy, who was permanently incapacitated by a lobotomy at age 23.