Purpose: To discern whether reduced infection rates were attributed to antiseptic solutions or mechanical rectal irrigation. Patients and Methods: After receiving ethical approval, the study included patients who underwent transrectal prostate biopsy due to elevated PSA or abnormal digital rectal examination findings, and prostate cancer under active surveillance, at Tepecik Training and Research Hospital between April 2022 and June 2023. Standard antibiotic prophylaxis was administered. Patients were randomized into three equal groups according to the rectal irrigation strategy. Results: Overall complications occurred in 4%. Despite distinct cleaning agents, there was no significant difference in infection rates ( p = 0.780) or fever incidence ( p = 0.776). Pathological analyses revealed comparable outcomes ( p = 0.764). Conclusion: The study challenges the prevailing belief that antiseptic solutions are indispensable for infection prevention, as saline demonstrated similar efficacy. Limitations include data gaps from potential external hospital visits and absent rectal microorganism swab culture. While TRUS-PB remains the gold standard, this study suggests that mechanically cleansing the rectal mucosa with saline—a cost-effective, side-effect-free alternative—may be a viable infection prevention method, particularly beneficial for patients with antiseptic allergies. The findings prompt a reconsideration of the necessity of antiseptic solutions in TRUS-PB, offering an alternative approach to mitigate infectious complications.