Vitamin B12 deficiency is an urgent public health problem that disproportionately affects individuals in low- and middle-income settings, where the burden of neglected tropical diseases (NTDs) is also unacceptably high. Emerging evidence supports a potential role of micronutrients in modulating the risk and severity of NTDs. However, the role of vitamin B12 in NTD pathogenesis is unknown. This systematic review was conducted to evaluate the evidence on the role of vitamin B12 in the etiology of NTDs. Ten studies were included in this review: one study using an in vitro/animal model, eight observational human studies and one ancillary analysis conducted within an intervention trial. Most research to date has focused on vitamin B12 status and helminthic infections. One study examined the effects of vitamin B12 interventions in NTDs in animal and in vitro models. Few prospective studies have been conducted to date to examine the role of vitamin B12 in NTDs. The limited literature in this area constrains our ability to make specific recommendations. Larger prospective human studies are needed to elucidate the role of vitamin B12 in NTD risk and severity in order to inform interventions in at-risk populations.