Background: Following cardiovascular surgery, patients are at high risk of requiring systemic management in the intensive care unit (ICU), resulting in hospitalization-associated disability (HAD). Predicting the risk of HAD during the postoperative course is important to prevent susceptibility to cardiovascular events. Assessment of physical function during the ICU stay may be useful as a prediction index but has not been established. Methods: This prospective observational study conducted at a high-volume cardiovascular center included 236 patients (34% female; median age, 73 years) who required an ICU stay of at least 72 hours after surgery and underwent postoperative rehabilitation. HAD was defined as a decrease in the discharge Barthel index (BI) score of at least 5 points relative to the preadmission BI score. Physical Function ICU Test-scored (PFIT-s), Functional Status Score for the ICU (FSS-ICU), and Medical Research Council (MRC)-sumscore were used to assess physical function at ICU discharge. Results: HAD occurred in 58 (24.6%) of the 236 patients following cardiovascular surgery. The cut-off points for HAD were 7.5 points for the PFIT-s (sensitivity 0.80, specificity 0.59), 24.5 points for the FSS-ICU (sensitivity 0.57, specificity 0.66), and 59.5 points for the MRC-sumscore (sensitivity 0.93, specificity 0.66). Multivariate logistic regression analysis revealed a PFIT-s of >7.5 points (odds ratio [OR], 4.84; 95% CI, 2.39–9.80; p 0.001) and an MRC-sumscore of >59.5 points (OR, 2.43; 95% CI, 1.22–4.87; p = 0.012) as independent associated factors. Conclusions: We demonstrate that the PFIT-s and MRC-sumscore at ICU discharge may be helpful as a predictive indicator for HAD in patients having undergone major cardiovascular surgery.