In 1965 Smalley received his B.A. from the University of Michigan. In 1973 he successfully defended his Ph.D. dissertation at Princeton University. Smalley combined his classes and scientific investigations with work in the chemical industry where he gained engineering skills and managerial experience.

Having received his Ph.D., Smalley was employed by the University of Chicago where, together with his colleagues, he developed a new scientific direction: laser spectroscopy in supersonic flows. In 1976, he moved to Houston, Texas with his family and took the office of assistant professor at Rice University. Proceeding with his work in spectroscopy, Smalley analyses the composition of atomic clusters formed by the evaporation of various substances by laser and their subsequent cooling in supersonic flows. Using this technique, in 1985 he, in collaboration with his university colleague Robert Curl and Harold Kroto from the British University of Sussex, discovered new spherical forms of carbon: fullerenes. In the following decade Smalley continued to study fullerenes (in particular C28, C70 and endohedral fullerenes) and also studied the formation of carbon nanotubes in the presence of various catalysts.

Having received the Nobel Prize for the discovery of fullerenes Smalley convinced the management to open the Rice Centre for Nanoscience and Technology (CNST). His team developed a method for synthesis of nanotubes from carbon monoxide under high pressure and transferred this technology to the newly established company Carbon Nanotechnologies.

An active supporter of the promotion and popularisation of nanotechnology, Smalley at the same time entered into a sharp controversy with Eric Drexler, a nanotechnology activist who promoted the idea of molecular assembly robots. Smalley pointed at the fundamental problems that hinder the creation of self-replicating robots and raised concerns that the apocalyptic pictures drawn by Drexler could seriously weaken the support of nanotechnology in society.

In his last years, sick with leukaemia, Smalley tried to draw the attention of scientists and society to global challenges, the most serious of which, in his opinion, was the search for low-cost and clean energy sources. Despite his illness, he spared no effort to promote science and education under the motto "Be a scientist – save the world".