Nonhormonal medical therapies represent a viable treatment option for selected cases of male infertility. When a specific infectious etiology is identified, targeted antibiotic therapy should be initiated based on microbial identification and antibiotic susceptibility testing. In cases of urogenital inflammation, characterized by leukocytospermia or idiopathic oligo-astheno-teratozoospermia, particularly in patients with a history of urogenital inflammatory conditions, therapeutic strategies, including anti-inflammatory agents and probiotics, may be beneficial. Combination therapies may contribute to the improvement of semen quality. Despite their frequent clinical use, fluoroquinolone antibiotics (e.g., ciprofloxacin and levofloxacin) may exert detrimental effects on sperm function and, although effective in eliminating pathogens, may be insufficient to completely suppress the concomitant inflammatory process. Anti-inflammatory therapy is chiefly indicated for the symptomatic management of acute inflammation affecting the male accessory glands, whereas extended treatment in chronic inflammatory states should be avoided. In the presence of antisperm antibodies, glucocorticoids may be employed due to their capacity to suppress immune-mediated spermatogenic impairment. Antioxidants are most appropriately employed as adjunctive therapy in patients with confirmed oxidative stress, particularly when specific etiology-targeted treatments are unavailable. Furthermore, probiotic and prebiotic supplementation has emerged as a promising therapeutic strategy, with growing evidence indicating favorable effects on sperm parameters, redox balance, endocrine regulation, and inflammatory status.