Microbial infection poses a severe threat to male reproductive health, leading to a decline in fertility, reproductive dysfunction, and the well-being of individuals. This review aimed to provide a comprehensive understanding of the molecular and cellular mechanisms of microbial infection in altering male fertility and how the crosstalk of the microbial pathogens, host immune responses, and reproductive tissues could manifest in a spectrum of reproductive tract disorders, including urethritis, prostatitis, epididymitis, and orchitis, a leading cause of human infertility. Insight into the molecular mechanisms of pathogenesis in microbial infections reveals the nature of the infection and disease progression, as well as informs the search for suitable therapeutic targets, which is crucial for curbing the infection. Microbes" virulence factors, attachment, and immune evasion strategies are exploited to colonize, invade, and maintain their persistence within the male reproductive tract. The diagnosis of genital tract infections in male reproductive health involves a thorough work-up, including microbiological, molecular, serological, and imaging procedures, as detailed in this review. Antimicrobial therapy remains a crucial component in treating microbial infections affecting male reproductive health. Nevertheless, the emergence of resistance, frequent adverse effects, and an increasing number of therapeutic failures have fueled the search for novel therapeutic options. Targeting new drugs against emerging pathogens also requires a clear understanding of resistance mechanisms. Development of precision medicine approaches, immunomodulatory therapies, identification of novel therapeutic targets, and preventive strategies are expected to top the research priorities in the field of male reproductive health. In summary, a combined scientific effort is necessary to overcome the complex challenges posed by microbial infections in male reproductive health. This study will enhance our understanding of the molecular basis of disease pathogenesis, aid in the development of targeted therapeutic interventions, and ultimately lead to the adoption of preventive and prophylactic strategies to mitigate the effects of microbial infections on male reproductive health and fertility.