Smalley was married four times, to Judith Grace Sampieri (1968–1978), Mary L. Chapieski (1980–1994), JoNell M. Chauvin (1997–1998) and Deborah Sheffield (2005), and had two sons, Chad Richard Smalley (born June 8, 1969) and Preston Reed Smalley (born August 8, 1997).
In 1999, Smalley was diagnosed with cancer. Smalley died of leukemia, variously reported as non-Hodgkin's lymphoma and chronic lymphocytic leukemia, on October 28, 2005, at M.D. Anderson Cancer Center in Houston, Texas, at the age of 62.
Upon Smalley's death, the US Senate passed a resolution to honor Smalley, crediting him as the "Father of Nanotechnology."