Molybdenum diselenide (MoSe2)—a transition-metal dichalcogenide—is a promising nonprecious metal catalyst for the hydrogen evolution reaction (HER). However, practical application of MoSe2 for electrocatalytic HER is hindered by its poor electrical conductivity, its high overpotential, and the limited number of active sites. Specifically, while the edges of MoSe2 are highly active for HER, the basal plane, which constitutes most of the catalyst surface, is inert toward HER. Although prior studies have focused on improving the activity of MoSe2 either by promoting the formation of highly active basal-plane Se vacancies or by substitutional doping of metal atoms, the interaction between dopants and Se vacancies—whether beneficial or detrimental toward HER—has not been fully understood. Here, we employ density functional theory calculations to study the interplay between prototypical transition metal (TM) dopants (Mn, Fe, Co, and Ni) and Se vacancies, and the consequent influence on hydrogen adsorption (a descriptor of HER activity in acidic media) at basal planes, edges, and Se vacancy sites. We correlate trends in the free energies of hydrogen adsorption and Se vacancy formation with changes in the electronic structure of MoSe2 upon TM doping as well as structural changes arising because of TM dopant atoms. Broadly, our studies show that the studied electron-rich TM dopants favorably modify the electronic structure of MoSe2 basal planes toward HER and, additionally, electrochemical generation of Se vacancies becomes more facile on the doped basal plane and edges at smaller cathodic potentials. These newly formed Se vacancies are typically highly active toward HER and substitutional doping can be viewed as an avenue for defect-mediated activation of MoSe2.