Walker served his apprenticeship with a Watson Alcock, a surgeon in Stockton-on-Tees. He completed his studies in London and returned as an assistant to the same surgeon. However, he found surgery of the time very gruesome and decided to change career to pharmacy. At this time there was no minimum entry qualification into the profession, so he acquired experience with pharmacists in Durham and York. He set up business on the High Street of Stockton-on-Tees in 1819 when he was 38 years old. He has been described as a "smart, trim, dapper, little man."

He had a manufacturing laboratory at the back of the shop, and began to experiment with combustible materials, including phosphorus. He was a bachelor and one of many scientists searching for an alternative way to strike a light from the clumsy tinderbox used at that time.

He discovered that a mixture of antimony sulphide and potassium chloride would produce a flame when rubbed against a coarse surface. He began to sell 'friction lights' (wood splinters tipped with the mixture) in 1827, first to customers in the shop and later by mail throughout Great Britain. He did not advertise his invention extensively, instead news spread by word of mouth. They were sold in a little cylindrical tin with a piece of sandpaper. The matches were ignited by drawing them through the folded sandpaper. Lighting 'friction matches' was apparently not easy as the head tended to detach itself in the process of drawing it through the sandpaper.

Despite encouragement by Michael Faraday and friends, Walker decided not to patent his invention or to exploit it on a larger scale as he felt he had enough money for his own needs and wished the discovery to be used for the benefit of the public. He only produced the matches for three years and the credit for his invention was attributed only after his death in 1859.

Many people copied his invention including Samuel Jones, who named his 'Lucifer Matches', a name that is said to have been offensive to Walker.

Samuel Jones owned a shop at 201 The Strand, London, which he appropriately called 'The Lighthouse'. He was the first person to exploit the sale of matches commercially and his 'Lucifers' differed in no way from Walker's 'friction lights'. He too had no protection over the matches or the name and so suffered from competition from other chemists and druggists. He did patent another type of match, which he called his 'Prometheus match' (produced by Walker at an earlier date). This was a wood splinter with a potassium chlorate head, which when dipped into sulphuric acid burst into flame. He sold these as a series of paper quills with the acid in a tiny sealed glass container and tweezers to break the container.

Again 'Lucifers' lasted only for three or four years, but the name continued as a generic term for much longer. This is attributed to the fact that they were the first match to come into general use.

Yellow phosphorus used then in the manufacture of matches was a massive health hazard, exposed by the Salvation Army in 1890. William Booth founded his new model match-factory in 1891, where they used red instead of yellow phosphorus. He labelled them "Lights in Darkest England", but as they were more expensive they didn't catch on. The use of yellow phosphorus was finally banned in 1910.