Background and Objectives: Antimicrobial stewardship plays a key role in the surgical setting by reducing the incidence of healthcare-associated infections and limiting the emergence of antimicrobial resistance. Clinical Decision Support Systems (CDSSs), when integrated into routine practice, are valuable tools for optimizing antimicrobial prescribing. However, evidence regarding their impact on surgical patients, particularly across different specialties, remains limited. Materials and Methods: We conducted a quasi-experimental time series study in surgical patients at a primary-level hospital, evaluating the effect of a CDSS on postoperative antimicrobial therapy. The pre-intervention period included patients admitted from April 2017 to September 2020, and the post-intervention period included those admitted from October 2020 to March 2024. Antimicrobial consumption and expenditures were measured as defined daily doses (DDDs) per 1000 patient-days and euros (€) per 1000 patient-days, respectively. Subgroup analyses were performed by the surgical service. Clinical outcomes included mortality and length of stay (LOS). Results: Following CDSS implementation, overall antimicrobial consumption decreased by 4.4%. Significant reductions were observed in aminoglycosides (−52.0%), macrolides, lincosamides and streptogramins (−40.6%), and fluoroquinolones (−32.3%). Reductions were heterogeneous across surgical services, with significant reductions in Traumatology (−21.3%) and Urology (−14.3%). Expenditures decreased from 3185.4 to 2733.9€/1000 patient-days (−14.2%; p = 0.17). Mortality remained stable, whereas significant reductions in LOS were observed in Urology (5 to 4 days, p = 0.03) and traumatology (16 to 8.5 days, p < 0.01). During the post-intervention period, 476 stewardship recommendations were issued for 330 patients, with an acceptance rate of 76.1%. The most frequent interventions were discontinuation of antimicrobials (25.8%), transition to oral therapy (21.0%), and de-escalation (18.7%). Conclusions: Implementation of a CDSS in the surgical setting was associated with reduced antimicrobial consumption, a downward trend in expenditures, and high acceptance of stewardship recommendations. Mortality remained unchanged, while reductions in LOS in selected services support the safety and potential efficiency of this approach.