Patients presenting with acute coronary syndrome (ACS) are frequently co-morbid. However, there is limited data on how co-morbidity burden impacts their receipt of invasive management and subsequent outcomes. We analyzed all patients with a discharge diagnosis of ACS from the National Inpatient Sample (2004 to 2014), stratified by Charlson Co-morbidity Index (CCI) into 4 classes (CCI 0, 1, 2, and ≥3). Regression analyses were performed to examine associations between co-morbidity burden and receipt of invasive intervention and in-hospital clinical outcomes. Of all 6,613,623 ACS patients analyzed, the prevalence of patients with severe co-morbidity (CCI ≥3) increased from 10.8% (2004) to 18.1% (2014). CCI class negatively correlated with receipt of invasive management, with CCI ≥3 group being the least likely to receive coronary angiography and percutaneous coronary intervention (odds ratio (OR) 0.42 95% confidence interval [CI] 0.41 to 0.43 and OR 0.47, 95% CI 0.46 to 0.48, respectively). CCI class was independently associated with an increased risk of mortality and complications, especially CCI ≥3 that was associated with significantly increased odds of Major Acute Cardiovascular & Cerebrovascular Events (OR 1.70, 95% CI 1.66 to 1.75), mortality (OR 1.74, 95% CI 1.68 to 1.79), acute ischemic stroke (OR 2.35, 95% CI 2.23 to 2.46), and major bleeding (OR 1.64, 95% CI 1.59 to 1.69). Co-morbidity burden has significantly increased amongst those presenting with ACS over an 11-year period and correlates with reduced likelihood of receipt of invasive management and increased odds of mortality and adverse outcomes. In conclusion, objective assessment of co-morbidities using CCI score identifies high-risk ACS patients in whom targeted risk reduction strategies may reduce their inherent risk of mortality and complications.