He returned to Italy in 1858 he was appointed surgeon at Milan Hospital and professor of general pathology at the University of Pavia.

[1] In 1879, Mantegazza travelled to Norway with his colleague Stephan Sommier on a quest to collect "anthropological facts" about the Sámi.

[2] In 1897, he published his novel The Year 3000: A Dream; through this work he projected that future citizens would have air conditioning, renewable electricity, credit cards, and virtual-reality entertainment, as well as a massive war in Europe, which would be followed by peace, integration, and a unified currency.

[3] During a time when the popular and official science and culture in Italy were still influenced by the Roman Catholic Church, Mantegazza was a staunch liberal and defended the ideas of Darwinism in anthropology, his research having helped to establish it as the "natural history of man".

Mantegazza's natural history, however, must be considered to be from a racial or social Darwinist perspective, evident in his Morphological Tree of Human Races.

I sneered at the poor mortals condemned to live in this valley of tears while I, carried on the wings of two leaves of coca, went flying through the spaces of 77,438 words, each more splendid than the one before...An hour later, I was sufficiently calm to write these words in a steady hand: God is unjust because he made man incapable of sustaining the effect of coca all life long.

He also wrote the novel Testa ("Head", 1887), a sequel of renowned book Heart, by his friend Edmondo de Amicis.