Appointed professor of Hebrew and Oriental languages at the Hamburg Gymnasium, or preparatory school, in 1727, Reimarus made his house a cultural centre and meeting place for learned and artistic societies. His first important philosophical work was Abhandlungen von den vornehmsten Wahrheiten der natürlichen Religion (1754; “Treatises on the Principal Truths of Natural Religion”), a Deistic discussion of cosmological, biological–psychological, and theological problems. In Die Vernunftlehre (1756; “Doctrine of Reason”) he combated traditional Christian belief in revelation.

Reimarus' major work, Apologie oder Schutzschrift für die vernünftigen Verehrer Gottes (“Apologia or Defense for the Rational Reverers of God”), took 20 years to complete and was deliberately left unpublished until after his death. Gotthold Lessing (Lessing, Gotthold Ephraim) obtained fragments of the work from Reimarus' children for publication under the title Wolfenbütteler Fragmente in his own Zur Geschichte und Literatur (1774 and 1777). The appearance of the fragments aroused a controversy known as the Fragmentenstreit (German Streit, “quarrel”) that provoked both liberal and conservative criticism. Other fragments were published by several writers between 1787 and 1862, occasionally under pseudonyms.

Reimarus also offered a novel treatment of the life of Jesus. Jesus (Jesus Christ), he claimed, was a mere human afflicted by messianic illusions; after his death his body was stolen and hidden by his disciples to maintain his resurrection. Reimarus consistently denied miracles except for creation itself and claimed that the ethical doctrines necessary for the survival of human society were accessible to reason without the aid of revealed principles.