Background/Objectives: The real impact of prehabilitation in the healthcare setting is controversial due to the efficacy-effectiveness gap. The effectiveness of prehabilitation in real-world scenarios has been associated with program attrition and adherence. This study aimed to identify factors influencing adherence to a multimodal prehabilitation program for patients undergoing major surgery. Methods: This is a analysis of a prospective trial conceived to explore the implementation of prehabilitation in a real-life setting. Participants were patients enrolled in our multimodal prehabilitation program, candidates for major surgery, and at high risk for postoperative complications. Sociodemographic and clinical variables were studied, with adherence to the program as the primary outcome. Descriptive analyses were conducted to examine associations between adherence and the study variables. A binary logistic regression model was applied to identify predictors of adherence. Results: Among the 559 patients included in the study, 356 (63.7%) were labelled as adherent. The analysis revealed significant associations between adherence and working status, type of exercise program prescribed (p < 0.001), smoking status (p = 0.023), age (t = -3.00, p = 0.003), comorbidities (t = -2.19, p = 0.029), and self-reported physical activity (t = -2.45, p = 0.015). The logistic regression identified as independent factors the type of exercise prescription, smoking status, residential area, working status, and neoadjuvant therapy. The predictive model demonstrated good specificity (86.1%) but lower sensitivity (50.6%), suggesting its utility in identifying patients at risk of non-adherence. Conclusions: Multiple factors influence adherence in prehabilitation programs. Our model exhibited good accuracy and specificity, but poor sensitivity.