Casals was an ardent supporter of the Spanish Republican government. After its defeat in 1939, Casals vowed not to return to Spain until democracy had been restored, although he did not live to see the end of the Franco dictatorial regime.

Casals was born in El Vendrell, Tarragona, Catalonia. His father, Carlos Casals i Ribes (1852-1908), was a parish organist and choirmaster. He gave Casals instruction in piano, song, violin, and organ. He was also a very strict disciplinarian. When Casals was young his father would pull the piano out from the wall and have him and his brother, Arturo, stand behind it and name the notes and the scales that his father was playing. At age four Casals could play the violin, piano and flute; at the age of six he played the violin well enough to perform a solo in public. His first encounter with a cello-like instrument was from witnessing a local travelling Catalan musician, who played a cello-strung broom handle. Upon request, his father built him a crude cello, using a gourd as a sound-box. When Casals was eleven, he first heard the real cello performed by a group of traveling musicians, and decided to dedicate himself to the instrument.

In 1888 his mother, Pilar Defilló de Casals, who was born in Mayagüez, Puerto Rico of Catalonian ancestry, took him to Barcelona, where he enrolled in the Escola Municipal de Música. There he studied cello, theory, and piano. In 1890, when he was 13, he discovered in a second-hand sheet music store in Barcelona a tattered copy of Bach's six cello suites. He spent the next 13 years practicing them every day before he would perform them in public for the first time. He made prodigious progress as a cellist; on February 23, 1891 he gave a solo recital in Barcelona at the age of fourteen. He graduated from the Escola with honours five years later.

In 1893, another Spanish composer Isaac Albéniz heard him playing in a trio in a café and gave him a letter of introduction to the private secretary to María Cristina, the Queen Regent. Casals was asked to play at informal concerts in the palace, and was granted a royal stipend to study composition at the Conservatorio de Música y Declamación in Madrid with Víctor Mirecki. He also played in the newly organized Quartet Society.

In 1895 he went to Paris, where, having lost his stipend from Catalonia, he earned a living by playing second cello in the theater orchestra of the Folies Marigny. In 1896, he returned to Catalonia and received an appointment to the faculty of the Escola Municipal de Música in Barcelona. He was also appointed principal cellist in the orchestra of Barcelona's opera house, the Liceu. In 1897 he appeared as soloist with the Madrid Symphony Orchestra, and was awarded the Order of Carlos III from the Queen.

In 1899, Casals played at The Crystal Palace in London, and later for Queen Victoria at Osborne House, her summer residence, accompanied by Ernest Walker. On November 12 and December 17, 1899, he appeared as a soloist at Lamoureux Concerts in Paris, to great public and critical acclaim. He toured Spain and the Netherlands with the pianist Harold Bauer in 1900-1901; in 1901-1902 he made his first tour of the United States; and in 1903 toured South America.

On January 15, 1904, Casals was invited to play at the White House for President Theodore Roosevelt. On March 9 of that year he made his debut at Carnegie Hall in New York, playing Richard Strauss's Don Quixote under the baton of the composer. In 1906 he became associated with the talented young Portuguese cellist Guilhermina Suggia, who studied with him and began to appear in concerts as Mme. P. Casals-Suggia, although they were not legally married. Their relationship ended in 1912.

The New York Times of April 9, 1911 announced that Pablo Casals would perform at the London Musical Festival to be held at the Queen's Hall on the second day of the Festival (May 23). The piece chosen was Haydn's Cello Concerto in D and Casals would later join Fritz Kreisler for Brahms's Double Concerto for Violin and Cello.

In 1914 Casals married the American socialite and singer Susan Metcalfe; they were separated in 1928, but did not divorce until 1957.

Although Casals made his first recordings in 1915 (a series for Columbia), it would not be until 1926 that he again released a recording (on the Victor label).