Fisher, a Londoner by birth, studied mathematics and physics at Cambridge University, graduating in 1912. In the years before joining Rothamsted Experimental Station in 1919 he undertook a variety of jobs, including farm work in Canada, employment with an investment company, and teaching in various private schools. In this period he also produced two important papers marking his interest in both statistics and genetics. The first, published in 1915, described a solution for the exact distribution of the correlation coefficient, a problem that had been perplexing other statisticians. The second paper was The Correlation between Relatives on the Supposition of Mendelian Inheritance (1918). This demonstrated that the inheritance of continuous variation, which had been thought of as non-Mendelian, is in fact governed by many additive genes, each of small effect and each inherited in a Mendelian manner. Thus continuous variation may be analyzed following Mendelian rules. This work later led to the development of the science of biometric genetics. At Rothamsted, Fisher was appointed to sort out the accumulation of over 60 years' data on field trials. He modified the significance test, enabling more confident conclusions to be drawn from small samples of data, and developed the analysis of variance technique. He emphasized the need for random rather than systematic experimental design so that error due to environmental variation could be analyzed quantitatively. His book Statistical Methods for Research Workers (1925) is one of the most influential works in statistics.

Fisher's major researches in genetics at Rothamsted were brought together in The Genetical Theory of Natural Selection (1930). In this book he argued that Mendelism, far from contradicting Darwinism as some people believed, actually provides the missing link in the theory of evolution by natural selection by showing that inheritance is particulate rather than blending. (In 1936 Fisher published a paper arguing that probabilistically Mendel's famous results were “too good to be true.”) The book also summarizes his views on eugenics and on genes controlling dominant characteristics. He believed that dominance develops gradually by selection, showing selection rather than mutation to be the driving force in evolution.

The Genetical Theory of Natural Selection led to Fisher's appointment as Galton Professor of Genetics at University College, London, in 1933. Here he did important work clarifying the genetics of the Rhesus blood groups. He accepted the chair of genetics at Cambridge University in 1943, remaining there until 1959 although he retired officially in 1957. He spent the last three years of his life working for the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Adelaide. Fisher was knighted in 1952.