For a person with a disability, participating in sports activities and/or competitions can be a challenge for the immune system. The relationship between exercise and immunity response in disabled athletes is, indeed, extremely complex for several reasons, including (1) the chronic low-grade inflammatory and immunodepression—“secondary immune deficiency”—state imposed by the disability/impairment; (2) the impact of the disability on an array of variables, spanning from physical fitness to well-being, quality of life, sleep, and nutritional aspects, among others, which are known to mediate/modulate the effects of exercise on human health; (3) the variability of the parameters related to the exercise/physical activity (modality, frequency, intensity, duration, training versus competition, etc.); and (4) the intra- and inter-individual variability of the immunological response to exercise. In able-bodied athletes, previously published data described several exercise-induced changes affecting various immunological subsets and subpopulations, ranging from neutrophils to lymphocytes, and monocytes. Broadly, moderate intensity workout is accompanied by optimal immunity and resistance to infections such as upper respiratory tract infections (URTI) in athletes. Periods of intense training with insufficient recovery can cause a temporary state of immunosuppression, which should end with a few days of rest/recovery from exercise. Disabled athletes are relatively overlooked and understudied with respect to their able-bodied counterparts. Findings from the few studies available on paralympic and disabled athletes are here summarized and analyzed utilizing a narrative approach to review and determine the major features of the immunological and inflammatory responses to exercise in this specific population. Moreover, a few studies have reported behavioral, dietary, and training strategies that can be adopted to limit exercise-induced immunosuppression and reduce the risk of infection in people with disabilities. However, given the paucity of data and contrasting findings, future high-quality investigations on paralympic and disabled athletes are urgently needed.