Background Antimicrobial stewardship program (ASP) surveillance at our hospital is supplemented by an internally developed surveillance database. In 2013, the database incorporated a validated, internally developed, prediction rule for patient mortality within 30 days of hospital admission. This study describes the impact of an expanded ASP review in patients at the highest risk for mortality. Methods This retrospective, quasi-experimental study analyzed adults who received antimicrobials with the highest mortality risk score. Study periods were defined as 2011 – Q3 2013 (historical group) and Q4 2013 – 2018 (intervention group). Primary and secondary outcomes were assessed for confounders and analyzed using both unadjusted and propensity score weighted analyses. Interrupted time-series analyses also analyzed key outcomes. Results A total of 3,282 and 5,456 patients were included in the historical and intervention groups, respectively. There were significant reductions in median antimicrobial duration (5 vs. 4 days; p < 0.001), antimicrobial DOTs (8 vs. 7; p < 0.001), antimicrobial cost ($96 vs. $85; p = 0.003), length of stay (LOS) (6 vs. 5 days; p < 0.001), intensive care unit (ICU) LOS (3 vs. 2 days; p < 0.001), total hospital cost ($10,946 vs. $9,119; p < 0.001), healthcare facility-onset vancomycin-resistant Enterococcus (HO-VRE) spp. (1.3% vs. 0.3%; p = < 0.001) and HO-VRE infections (0.6% vs. 0.2%; p = 0.018) in the intervention cohort. Conclusion Reductions in antimicrobial use, hospital and ICU LOS, HO-VRE, HO-VRE infections, and costs were associated with incorporation of a novel mortality prediction rule to guide ASP surveillance and intervention.