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Cullen was born in Hamilton, Lanarkshire. His father William was a lawyer retained by the Duke of Hamilton as factor, and his mother was Elizabeth Roberton of Whistlebury. He studied at the Old Grammar School of Hamilton (renamed in 1848 The Hamilton Academy), then, in 1726, began a General Studies arts course at the University of Glasgow. He began his medical training as apprentice to John Paisley, a Glasgow apothecary surgeon, then spent 1729 as surgeon on a merchant vessel trading between London and the West Indies.

According to Rocca, Cullen was known for systemizing and promoting medical knowledge rather than producing original research. Despite the lack of original work, some believed that Cullen's attempt to organize existing knowledge was actually a sign of his "practical sagacity" as a practitioner. He was a lecturer for more than forty years. In order to understand Cullen's medical teaching at the time, it is important to understand Cullen's conception of "system" as he taught it in his classes. Cullen described a system as "an organised body of opinions on particular topics in the medical curriculum." He also referred to system as the principles in his book First Lines of the Practice of Physic. There were many possible reasons behind Cullen's emphasis of the system of medicine. In the 18th century, a period of Scottish Enlightenment, there were competing theories about the mechanisms of the human body and the causes of diseases proposed by different professors, who competed for students' teaching fees. Thus, having an underlying system of medical knowledge was a practical way to organize the knowledge coherently for the students.  Like many prominent medical figures in the 18th century, William Cullen took a great interest in the nervous system. He defined the nervous system as an "animated machine" whose main function is to "perform a variety of motions," communicate and interact with "external bodies." Cullen believed that the nervous system was composed of four elements: the medullary substance, consisting of the brain and the spinal cord, the membranous nerves, the sensory nerves, and the muscular fibers.  Cullen's understanding of the nervous system was also influenced by his contemporaries, one of whom was Albrecht von Haller (1708-1777). Haller proposed that tissues, including muscles, were characterized by "irritability" (or contractility), while nerves were characterized by "sensibility" (or feeling). Using Haller's characterization, Cullen defined disease "as an excess or deficiency of sensibility." However, Cullen interpreted sensibility as "muscle mobility and vigour" and diseases were caused by the imbalance of irritability and sensibility. Based on this definition of disease, his therapeutics "either stimulated or sedated the nervous system." He categorized diseases into four main classes: pyrexiae, neuroses, cachexiae, and locales. Within the classes were nineteen orders and 132 genera. The four orders of neuroses were comata, adynamiae, spasmi and vesaniae. Comata was defined as "a diminution of voluntary motion, with sleep, or a deprivation of the senses." Adynamiae is defined as "a diminution of the involuntary motions, whether vital or natural." Spasmi was defined as "irregular motions of the muscles or muscular fibers." Vesaniae was defined as "disorders of the judgement without any pyrexia or coma."  Cullen's emphasis on the importance of the nervous system was driven by the understanding that the nervous system controls the human body and therefore, "all diseases may, in some sense, be called affections of the nervous system, because, in almost every disease, the nerves are more or less hurt." Although Cullen's nosology did not last very long, Cullen's influential teachings on medical knowledge and his attempt to systematize and generalize medical knowledge were integral parts of 18th century Scottish Enlightenment.
William Cullen