Background β-Lactam antibiotics are first-line therapy for perioperative prophylaxis; however, patient-reported allergies often lead to increased prescribing of alternative antibiotics that may increase the incidence of surgical site infections. The R-group side chain of the β-lactam ring is responsible for allergic cross-reactivity and experts recommend the use of β-lactams that are structurally dissimilar. Methods An internally developed, antibiotic side-chain–based cross-reactivity chart was developed and implemented alongside enhanced allergy assessment processes. This single-center, quasi-experimental study analyzed antibiotic prescribing in all adult patients with a documented β-lactam allergy undergoing an inpatient surgical procedure between quartile (Q) 1 (2012)–Q3 (2014) (historical group) and Q3 (2016)–Q3 (2018) (intervention group). Propensity-weighted scoring analyses compared categorical and continuous outcomes. Interrupted time-series analysis further analyzed key outcomes. Results A total of 1119 and 1089 patients were included in the historical and intervention cohorts, respectively. There was a significant difference in patients receiving a β-lactam alternative antibiotic between cohorts (84.9% vs 15.1%; P < .001). There was a decrease in 30-day readmissions in the intervention cohort (7.9% vs 6.3%; P = .035); however, there was no difference in the incidence of SSIs in patients readmitted (14.8% vs 13%; P = .765). No significant differences were observed in allergic reactions (0.5% vs 0.3%; P = .323), surgical site infections, in-hospital and 30-day mortality, healthcare facility–onset Clostridiodes difficile infection, acute kidney injury, or hospital costs. Conclusions Implementation of an antibiotic cross-reactivity chart combined with enhanced allergy assessment processes significantly improved the prescribing of β-lactam antibiotics for surgical prophylaxis.