Born at Rochester, Littlewood studied at Cambridge University and in 1907 obtained a lectureship at Manchester. By 1910 he had returned to Cambridge where in 1928 he became Rouse Ball Professor of Mathematics. He retired in 1950 but continued active mathematical research until shortly before his death.

Littlewood is primarily known for his work in analysis, but he made contributions to many other fields, including mathematical astronomy, physics, differential equations, and probability theory. One of the most notable features of his career was his 35-year collaboration with G. H. Hardy. Among their most important joint work was the systematic investigation of problems of the convergence and summability of Fourier series. In 1914 Littlewood proved a famous theorem about the error term in the prime number theorem. In collaboration with R. E. A. C. Paley, Littlewood created and developed a new and specific link between trigonometric series and analytical functions. His work with Mary Cartwright on nonlinear differential equations was also of importance.