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Simple Summary: The choice between a transrectal or a transperineal approach for MRI-fusion-targeted prostate biopsy is still the subject of debate within the urologic community and across international Guidelines. Specifically, the European Association of Urology (EAU) guidelines recommend abandoning TRPB in favor of TPPB, due to lower rates of infection and sepsis. In contrast, the American Urological Association (AUA) recommends either approach, citing the absence of prospective RCTs assessing infectious risk. In this scenario, transparent reporting of the morbidity of the transrectal prostate biopsy is crucial to inform patients during shared decision-making and to evaluate the cost-effectiveness of different biopsy approaches from clinical and economic standpoints. Despite transrectal prostate biopsy (TRPB) being still widespread globally, the EAU Guidelines strongly recommend the transperineal approach, due to the reported lower infectious risk. Our study aims to evaluate the impact of a standardized clinical pathway for TRPB on post-operative complications. We prospectively collected data from all patients undergoing mpMRI-targeted TRPB at our Academic Centre from January 2020 to December 2022. All patients followed a standardized, structured multistep pathway. Post-procedural complications were collected and classified according to the Clavien–Dindo (CD) Classification. Among 458 patients, post-procedural adverse events were reported by 203 (44.3%), of which 161 (35.2%) experienced CD grade 1 complications (hematuria [124, 27.1%], hematochezia [22, 4.8%], hematospermia [14, 3.1%], or a combination [20, 4.4%]), and 45 (9.0%) reported CD grade 2 complications (acute urinary retention or hematuria needing catheterization, as well as urinary tract infections, of which 2 cases required hospitalization). No major complications, including sepsis, were observed. At uni- and multivariable analysis, age > 70 years and BMI > 25 kg/ m2 for patients were identified as predictors of post-operative complications. The results of our study confirm that TRPB is a safe and cost-effective procedure with a low risk of severe adverse events in experienced hands and following a standardized pathway. [ABSTRACT FROM AUTHOR]