Mortality in patients with STEMI-associated cardiogenic shock (CS) is increasing. Whether a comprehensive ST-elevation myocardial infarction (STEMI) protocol (CSP) can improve their care delivery and mortality is unknown. We evaluated the impact of a CSP on incidence and outcomes in patients with STEMI-associated CS. We implemented a 4-step CSP including: (1) Emergency Department catheterization lab activation; (2) STEMI Safe Handoff Checklist; (3) immediate catheterization lab transfer; (4) and radial-first percutaneous coronary intervention (PCI). We studied 1,272 consecutive STEMI patients who underwent PCI and assessed for CS incidence per National Cardiovascular Data Registry definitions within 24-hours of PCI, care delivery, and mortality before (January 1, 2011, to July 14, 2014; n = 723) and after (July 15, 2014, to December 31, 2016; n = 549) CSP implementation. Following CSP implementation, CS incidence was reduced (13.0% vs 7.8%, p = 0.003). Of 137 CS patients, 43 (31.4%) were in the CSP group. CSP patients had greater IABP-Shock II risk scores (1.9 ± 1.8 vs 2.8 ± 2.2, p = 0.014) with otherwise similar hemodynamic and baseline characteristics, cardiac arrest incidence, and mechanical circulatory support use. Administration of guideline-directed medical therapy was similar (89.4% vs 97.7%, p = 0.172) with significant improvements in trans-radial PCI (9.6% vs 44.2%, p < 0.001) and door-to-balloon time (129.0 [89:160] vs 95.0 [81:116] minutes, p = 0.001) in the CSP group, translating to improvements in infarct size (CK-MB 220.9 ± 156.0 vs 151.5 ± 98.5 ng/ml, p = 0.005), ejection fraction (40.8 ± 14.5% vs 46.7 ± 14.6%, p = 0.037), and in-hospital mortality (30.9% vs 14.0%, p = 0.037). In conclusion, CSP implementation was associated with improvements in CS incidence, infarct size, ejection fraction, and in-hospital mortality in patients with STEMI-associated CS. This strategy offers a potential solution to bridging the historically elusive gap in their care.