He worked on topics relating to analysis, number theory, and differential equations and had lengthy collaborations with G. H. Hardy, Srinivasa Ramanujan and Mary Cartwright.

[1] In 1892, his father accepted the headmastership of a school in Wynberg, Cape Town, in South Africa, taking his family there.

[2] Littlewood returned to Britain in 1900 to attend St Paul's School in London, studying under Francis Sowerby Macaulay, an influential algebraic geometer.

He was president of the London Mathematical Society from 1941 to 1943 and was awarded the De Morgan Medal in 1938 and the Senior Berwick Prize in 1960.

However, the link between the Riemann hypothesis and the prime number theorem had been known before in Continental Europe, and Littlewood wrote later in his book, A Mathematician's Miscellany that his rediscovery of the result did not shed a positive light on the isolated nature of British mathematics at the time.

[7][8] In 1914, Littlewood published his first result in the field of analytic number theory concerning the error term of the prime-counting function.

[11] In the late 1930s, as the prospect of war loomed, the Department of Scientific and Industrial Research sought the interest of pure mathematicians in the properties of non linear differential equations that were needed by radio engineers and scientists.

Littlewood's collaborative work, carried out by correspondence, covered fields in Diophantine approximation and Waring's problem, in particular.

In a 1947 lecture, the Danish mathematician Harald Bohr said, "To illustrate to what extent Hardy and Littlewood in the course of the years came to be considered as the leaders of recent English mathematical research, I may report what an excellent colleague once jokingly said: 'Nowadays, there are only three really great English mathematicians: Hardy, Littlewood, and Hardy–Littlewood.'

[17] He coined Littlewood's law, which states that individuals can expect "miracles" to happen to them at the rate of about one per month.