Background The burden of frail patients undergoing emergency general surgery (EGS) is increasing rapidly and this population is particularly susceptible to postoperative cardiopulmonary complications and mortality. We aimed to determine the association between frailty, as defined by the previously described modified frailty index (mFI), and postoperative respiratory complications (unplanned reintubation, pneumonia, and prolonged ventilation), cardiac complications (myocardial infarction and cardiac arrest), and mortality. We also sought to identify the most significant determinants of frailty in the highest risk patients based on the specific variables comprising the mFI. Methods We performed a retrospective observational analysis of the prospectively collected American College of Surgeons National Surgical Quality Improvement Program database. Files from 2005 to 2015 identified 132,765 inpatients who underwent EGS. mFI scores were calculated for each patient. The effect of increasing frailty on unplanned reintubation, pneumonia, prolonged ventilation, myocardial infarction, cardiac arrest, and mortality was evaluated using bivariate analysis. Multivariable logistic regression was used to compare mFI with additional predictor variables including race, gender, physical status as defined by the American Society of Anesthesiologists, disseminated cancer, renal failure, smoking status, sepsis, wound presence/classification, dyspnea, and previous ventilator dependence. Results Unplanned reintubation, pneumonia, prolonged ventilation, myocardial infarction, cardiac arrest, and mortality were significantly associated with frailty, and the odds of each postoperative complication increased with increasing mFI score. Of the frailest patients (mFI ≥3) that experienced cardiopulmonary complications or mortality, the variables of the mFI that contributed most to frailty were hypertension requiring medication and functional status before surgery. Conclusions A higher mFI score is associated with increased odds of postoperative cardiopulmonary complications and mortality in the EGS population. Specific variables of the mFI can also provide valuable information for assessing odds in the frailest patients undergoing EGS.