Official biographies claim Charles Scott Sherrington was born in Islington, London, England, on 27 November 1857 and that he was the son of James Norton Sherrington, a country Doctor, and his wife Anne Thurtell. However James Norton Sherrington was an ironmonger and artist's colourman in Great Yarmouth, not a Doctor, and died in Yarmouth in 1848, nearly 9 years before Charles was born. In the 1861 census, Charles is recorded as Charles Scott (boarder, 4, born India) with Anne Sherrington (widow) as the head and Caleb Rose (visitor, married, surgeon). He was brought up in this household with Caleb recorded as head in 1871, although Ann and Caleb did not marry until after the death of his wife in 1880. The relationship between Charles and his childhood family is unknown. During the 1860s the whole family moved to Anglesea Road, Ipswich, reputedly because London exacerbated Caleb Rose's tendency to asthma.

Sherrington entered Ipswich School in 1871. Thomas Ashe, a famous English poet, worked at the school. Ashe served as an inspiration to Sherrington, the former instilling a love of classics and a Desire to travel in the latter.

Sherrington played football for his grammar school, and for Ipswich Town Football Club, rugby St. Thomas's, was on the rowing team at Oxford. During June 1875, Sherrington passed his preliminary examination in general education at the Royal College. This preliminary exam was required for Fellowship, and also exempted him from a similar exam for the Membership. In April 1878, he passed his Primary Examination for the Membership of the Royal College of Surgeons, and 12 months later the Primary for Fellowship.

Rose had pushed Sherrington towards Medicine. Sherrington first began to study with the Royal College of Surgeons of England. He also sought to study at Cambridge, but a bank failure had devastated the family's finances. Sherrington elected to enroll at St Thomas' Hospital in September 1876 as a "perpetual pupil". He did so in order to allow his two younger brothers to do so ahead of him. The two studied law there. Medical studies at St. Thomas's Hospital were intertwined with studies at Gonville and Caius College, Cambridge. Physiology was Sherrington's chosen major at Cambridge. There, he studied under the "father of British physiology," Sir Michael Foster.

In October 1879, Sherrington entered Cambridge as a non-collegiate student. The following year he entered Gonville and Caius College. Sherrington was quite the student. In June 1881 he took Part I in the Natural Sciences Tripos and was awarded a starred First in physiology; there were 9 candidates in all (8 men, 1 woman), of whom five gained Firsts; in June 1883 in Part II of the Tripos he also gained a First, alongside william Bateson. Walter Holbrook Gaskell, one of Sherrington's tutors, informed him in November 1881 that he had earned the highest marks for his year in botany, human anatomy, and physiology; second in zoology; and highest overall. John Newport Langley was Sherrington's other tutor. The two were interested in how anatomical structure is expressed in physiological function.

The conference was held in London in 1881. It was at this conference that Sherrington began his work in neurological research. At the conference controversy broke out. Friedrich Goltz of Strasbourg argued that localized function in the cortex did not exist. Goltz came to this conclusion after observing dogs who had parts of their brains removed. David Ferrier, who became a hero of Sherrington's, disagreed. Ferrier maintained that there was localization of function in the brain. Ferrier's strongest evidence was a monkey who suffered from hemiplegia, paralysis affecting one side of the body only, after a cerebral lesion.

In the Winter of 1884–1885, Sherrington left England for Strasbourg. There, he worked with Goltz. Goltz, like many others, positively influenced Sherrington. Sherrington later said of Goltz that: "[h]e taught one that in all things only the best is good enough."

A case of asiatic cholera had broken out in Spain in 1885. A Spanish physician claimed to have produced a vaccine to fight the outbreak. Under the auspices of Cambridge University, the Royal Society of London, and the Association for Research in Medicine, a group was put together to travel to Spain to investigate. C.S. Roy, J. Graham Brown, and Sherrington formed the group. Roy was Sherrington's friend and the newly elected professor of pathology at Cambridge. As the three traveled to Toledo, Sherrington was skeptical of the Spanish physician. Upon returning, the three presented a report to the Royal Society. The report discredited the Spaniard's claim.

In 1886, Sherrington went to Italy to again investigate a cholera outbreak. While in Italy, Sherrington spent much time in art galleries. It was in this country that Sherrington's love for rare books became an addiction.

On 27 August 1891, Sherrington married Ethel Mary Wright (d.1933). Wright was the daughter of John Ely Wright of Preston Manor, Suffolk, England. Sherrington and Wright had one child, a son named Charles E.R. (Carr) Sherrington who was born in 1897. Wright was both loyal and lively. She was a great host. On weekends during the Oxford years the couple would frequently host a large group of friends and acquaintances at their house for an enjoyable afternoon.

Sherrington was elected a Fellow of the Royal Society (FRS) in 1893.

As early as 1895, Sherrington had tried to gain employment at Oxford University. By 1913, the wait was over. Oxford offered Sherrington the Waynflete Chair of Physiology. The electors to that chair unanimously recommended Sherrington without considering any other candidates. Sherrington enjoyed the honor of teaching many bright students at Oxford, including Wilder Penfield, who he introduced to the study of the brain. Several of his students were Rhodes scholars, three of whom - Sir John Eccles, Ragnar Granit, and Howard Florey - went on to be Nobel laureates. Sherrington also influenced American pioneer brain surgeon Harvey Williams Cushing.

Sherrington showed that muscle excitation was inversely proportional to the inhibition of an opposing group of muscles. Speaking of the excitation-inhibition relationship, Sherrington said "desistence from action may be as truly active as is the taking of action." Sherrington continued his work on reciprocal innervation during his years at Liverpool. Come 1913, Sherrington was able to say that "the process of excitation and inhibition may be viewed as polar opposites [...] the one is able to neutralize the other." Sherrington's work on reciprocal innervation was a notable contribution to the knowledge of the spinal cord.

In March 1916, Sherrington fought for women to be admitted to the medical school at Oxford.

Charles Sherrington retired from Oxford in the year of 1936. He then moved to his boyhood town of Ipswich, where he built a house. There, he kept up a large correspondence with pupils and others from around the world. He also continued to work on his poetic, historical, and philosophical interests. From 1944 until his own death he was President of the Ipswich Museum, on the committee of which he had previously served.

Sherrington's mental faculties were crystal clear up to the time of his sudden death, which was caused by a sudden heart failure at age 94. His bodily health, however, did suffer in old age. Arthritis was a major burden of his. Speaking of his condition, Sherrington said "old age isn't pleasant[,] one can't do things for oneself." The arthritis put Sherrington in a nursing home in the year before his death, in 1951.

While at Oxford, Sherrington kept hundreds of microscope slides in a specially constructed box labelled "Sir Charles Sherrington's Histology Demonstration Slides". As well as histology demonstration slides, the box contains slides which may be related to original breakthroughs such as cortical localization in the brain; slides from contemporaries such as Angelo Ruffini and Gustav Fritsch; and slides from colleagues at Oxford such as John Burdon-Sanderson – the first Waynflete Chair of Physiology – and Derek Denny-Brown, who worked with Sherrington at Oxford (1924–1928)).