His baptism followed on 3 May in the river Lark, at Isleham. Later that same year he moved to Cambridge, where he later became a Sunday school Teacher. He preached his first sermon in the winter of 1850–51 in a cottage at Teversham while filling in for a friend. From the beginning of his ministry his style and ability were considered to be far above average. In the same year, he was installed as pastor of the small Baptist church at Waterbeach, Cambridgeshire, where he published his first literary work, a Gospel tract written in 1853.

In April 1854, after preaching three months on probation and just four years after his conversion, Spurgeon, then only 19, was called to the pastorate of London's famed New Park Street Chapel, Southwark (formerly pastored by the Particular Baptists Benjamin Keach, theologian John Gill and John Rippon). This was the largest Baptist congregation in London at the time, although it had dwindled in numbers for several years. Spurgeon found friends in London among his fellow Pastors, such as william Garrett Lewis of Westbourne Grove Church, an older man who along with Spurgeon went on to found the London Baptist Association.

Immediately following his fame was criticism. The first attack in the press appeared in the Earthen Vessel in January 1855. His preaching, although not revolutionary in substance, was a plain-spoken and direct appeal to the people, using the Bible to provoke them to consider the teachings of Jesus Christ. Critical attacks from the media persisted throughout his life. The congregation quickly outgrew their building, and moved to Exeter Hall, then to Surrey Music Hall. In these venues Spurgeon frequently preached to audiences numbering more than 10,000. At 22, Spurgeon was the most popular preacher of the day.

On 8 January 1856, Spurgeon married Susannah, daughter of Robert Thompson of Falcon Square, London, by whom he had twin sons, Charles and Thomas born on 20 September 1856. At the end of that year, tragedy struck on 19 October 1856, as Spurgeon was preaching at the Surrey Gardens Music Hall for the first time. Someone in the crowd yelled, "Fire!" The ensuing panic and stampede left several dead. Spurgeon was emotionally devastated by the event and it had a sobering influence on his life. For many years he spoke of being moved to tears for no reason known to himself.

Spurgeon's work went on. A Pastors' College was founded in 1857 by Spurgeon and was renamed Spurgeon's College in 1923, when it moved to its present building in South Norwood Hill, London. At the Fast Day, 7 October 1857, he preached to the largest crowd ever – 23,654 people – at The Crystal Palace in London. Spurgeon noted:

On 18 March 1861, the congregation moved permanently to the newly constructed purpose-built Metropolitan Tabernacle at Elephant and Castle, Southwark, seating 5000 people with standing room for another 1000. The Metropolitan Tabernacle was the largest church edifice of its day. Spurgeon continued to preach there several times per week until his death 31 years later. He never gave altar calls at the conclusion of his sermons, but he always extended the invitation that if anyone was moved to seek an interest in Christ by his preaching on a Sunday, they could meet with him at his vestry on Monday morning. Without fail, there was always someone at his door the next day.

On 5 June 1862, Spurgeon challenged the Church of England when he preached against baptismal regeneration. However, Spurgeon taught across denominational lines as well: for Example, in 1877 he was the preacher at the opening of a new Free Church of Scotland church building in Dingwall. It was during this period at the new Tabernacle that Spurgeon found a friend in James Hudson Taylor, the founder of the inter-denominational China Inland Mission. Spurgeon supported the work of the mission financially and directed many missionary candidates to apply for Service with Taylor. He also aided in the work of cross-cultural evangelism by promoting "The Wordless Book", a teaching tool that he described in a message given on 11 January 1866, regarding Psalm 51:7: "Wash me, and I shall be whiter than snow." The book has been and is still used to teach people without reading skills and people of other cultures and languages – young and old – around the globe about the Gospel message.

Besides sermons, Spurgeon also wrote several hymns and published a new collection of worship songs in 1866 called "Our Own Hymn Book". It was mostly a compilation of Isaac Watts's Psalms and Hymns that had been originally selected by John Rippon, a Baptist predecessor to Spurgeon. Singing in the congregation was exclusively a cappella under his pastorate. Thousands heard the preaching and were led in the singing without any amplification of sound that exists today. Hymns were a subject that he took seriously. While Spurgeon was still preaching at New Park Street, a hymn book called "The Rivulet" was published. Spurgeon aroused controversy because of his critique of its theology, which was largely deistic. At the end of his review, Spurgeon warned:

Following the Example of George Müller, Spurgeon founded the Stockwell Orphanage, which opened for boys in 1867 and for girls in 1879, and which continued in London until it was bombed in the Second World War. The orphanage became Spurgeon's Child Care which still exists today. On the death of missionary David Livingstone in 1873, a discolored and much-used copy of one of Spurgeon's printed sermons, "Accidents, Not Punishments," was found among his few possessions much later, along with the handwritten comment at the top of the first page: "Very good, D.L." He had carried it with him throughout his travels in Africa. It was sent to Spurgeon and treasured by him.

A controversy among the Baptists flared in 1887 with Spurgeon's first "Down-grade" article, published in The Sword & the Trowel. In the ensuing "Downgrade Controversy," the Metropolitan Tabernacle became disaffiliated from the Baptist Union, effectuating Spurgeon's congregation as the world's largest self-standing church. Spurgeon framed the controversy in this way:

Spurgeon's wife was often too ill to leave home to hear him preach. Spurgeon also suffered ill health toward the end of his life, afflicted by a combination of rheumatism, gout and Bright's disease. He often recuperated at Menton, near Nice, France, where he died on 31 January 1892. He enjoyed cigars and smoked a "F. P Del Rio y Ca." in his last days according to his grandson. Spurgeon was survived by his wife and sons. His remains were buried at West Norwood Cemetery in London, where the tomb is still visited by admirers. His son Tom became the pastor of the Metropolitan Tabernacle after his father died.

Walter Thornbury later wrote in "Old and New London" (1897) describing a subsequent meeting at Surrey: