The discovery, by chance, of a buzzard's nest led him to the study of birds, and a meeting with Christian Ludwig Brehm.

At first Schlegel worked mainly on the reptile collection and wrote Essai sur la Physionomie des Serpens (1837), but soon his field of activity extended to other zoological groups.

[2][3][4] The English naturalist Charles Darwin knew of Schlegel's opinions on species and evolution from remarks by his close friend, the British botanist and explorer Joseph Dalton Hooker: ‘I talked much with Schlegel, he is strongly in favour of a multiple creation & against migration’.

[5] When Temminck died at the beginning of 1858, Schlegel succeeded him as director of the natural history museum, after having spent 33 years under his direction.

At the same time, he started to publish a scientific magazine, Notes from the Leyden Museum, as well as a vast work of 14 volumes, Muséum d'histoire naturelle des Pays-Bas (1862-1880).