Recent literature has shown that vitamin D, in addition to its well-known activity on the skeleton, has many positive effects on health. Unfortunately, it is not easy to meet intake needs solely with food. Mushrooms could provide a valid way to achieve this goal, because they are one of the few sources of vitamin D. The aim of this systematic review was to summarize what has been reported in the literature on the treatment of animal and human models with irradiated commercial mushrooms, with particular attention paid to the effects on clinical outcomes associated with the classical and nonclassical vitamin D functions. A total of 18 articles were selected. Six studies were conducted on human samples, while twelve were focused on animal models. The six studies conducted in humans involved a large number of subjects (663), but the treatment period was relatively short (1–6 months). Furthermore, the treatment dosage was different in the various groups (600–3800 IU/day). Probably for this reason, the studies did not demonstrate clinical efficacy on the parameters evaluated (cognitive functions, muscle system/function, metabolic syndrome). Indeed, those studies demonstrated an efficacy in increasing the blood levels of 25(OH)D2, but not in increasing the levels of 25(OH)D total. In 9 of 12 studies conducted on the animal model, however, a clinical efficacy on bone metabolism, inflammation, and cognitive performance was demonstrated. The results of this systematic review indicate that the intake of vitamin D from irradiated mushrooms could possibly help to meet vitamin D needs, but the dosage and the time of treatment tested need to be evaluated. Therefore, studies conducted in humans for longer periods than the studies carried out up to now are necessary, with defined dosages, in order to also evaluate the clinical efficacy demonstrated in animal models both for the classical (bone metabolism) and nonclassical (muscle function, cognitive performance, anti-inflammatory, and antioxidant activities) effects of vitamin D.