Born in Brand, Bavaria, Reger studied music theory in Sondershausen, then piano and theory in Wiesbaden. The first compositions to which he assigned opus numbers were chamber music and Lieder. A concert pianist himself, he composed works for both piano and organ. His first work for choir and piano to which he assigned an opus number was Drei Chöre.
Reger returned to his parental home in 1898, where he composed his first work for choir and orchestra, Hymne an den Gesang (Hymn to singing), Op. 21. From 1899, he courted Bercken who first rejected him. He composed many songs such as Sechs Lieder, Op. 35, on love poems by five authors. Reger moved to Munich in September 1901, where he obtained concert offers and where his rapid rise to fame began. During his first Munich season, Reger appeared in ten concerts as an organist, chamber pianist and accompanist. Income from publishers, concerts and private teaching enabled him to marry in 1902. Because his wife Elsa was a divorced Protestant, he was excommunicated from the Catholic Church. He continued to compose without interruption, for example Gesang der Verklärten, Op. 71.
In 1907, Reger was appointed musical director at the Leipzig University Church, a position he held until 1908, and professor at the Royal Conservatory in Leipzig. In 1908 he began to compose Der 100. Psalm (The 100th Psalm), Op. 106, a setting of Psalm 100 for mixed choir and orchestra, for the 350th anniversary of Jena University. Part I was premiered on 31 July that year. Reger completed the composition in 1909, premiered in 1910 simultaneously in both Chemnitz and Breslau.
In 1911 Reger was appointed Hofkapellmeister (music director) at the court of Duke Georg II of Saxe-Meiningen, responsible also for music at the Meiningen Court Theatre. He retained his master class at the Leipzig conservatory. In 1913 he composed four tone poems on paintings by Arnold Böcklin (Vier Tongedichte nach Arnold Böcklin), including Die Toteninsel (Isle of the Dead), as his Op. 128. He gave up the court position in 1914 for health reasons. In response to World War I, he thought in 1914 already to compose a choral work to commemorate the fallen of the war. He began to set the Latin Requiem but abandoned the work as a fragment. He composed eight motets forming Acht geistliche Gesänge für gemischten Chor (Eight Sacred Songs), Op. 138, as a master of "new simplicity". In 1915 he moved to Jena, commuting once a week to teach in Leipzig. He composed in Jena the Hebbel Requiem for soloist, choir and orchestra. Reger died of a heart attack while staying at a hotel in Leipzig on 11 May 1916. The proofs of Acht geistliche Gesänge, including "Der Mensch lebt und bestehet nur eine kleine Zeit", were found next to his bed.
Reger had also been active internationally as a conductor and pianist. Among his students were Joseph Haas, Sándor Jemnitz, Jaroslav Kvapil, Ruben Liljefors, Rudolf Serkin, George Szell and Cristòfor Taltabull.
Reger was the cousin of Hans von Koessler.