Significance The adenovirus capsid protein is built by three main capsomers: hexon, fiber, and penton base. Entry is mediated by fiber proteins anchoring the virus to host cell receptors and is followed by penton base proteins engaging coreceptors, resulting in entry. Here, we demonstrate that human adenovirus species D types, which constitute two-thirds of all human adenoviruses, enter host cells through a direct interaction between the hexon protein and CD46. This study provides insights into the entry mechanisms used by human adenoviruses. As these viruses are also used as vaccine vectors for prevention of other infectious diseases, the results provided will also be useful for further development of human adenovirus species D types as vaccine vectors.