Muscle loss in critically ill patients, particularly during prolonged ICU stays, poses significant challenges to recovery and long-term outcomes. ICU-acquired weakness (ICUAW) manifests as severe muscle depletion, correlating with illness severity and hospitalization duration. This study aims to characterize long-term muscle loss trajectories in ICU patients with acute respiratory distress syndrome (ARDS) due to COVID-19 and severe acute pancreatitis (AP) and to explore contributing factors to elevated muscle decay. Retrospective cohort study including 154 ICU patients, 100 individuals suffering from AP and 54 from COVID-19 ARDS, who underwent a minimum of three CT scans during hospitalization, totaling 988 assessments. Sequential segmentation of psoas muscle area (PMA) was performed, and relative muscle loss per day for the entire monitoring period, as well as for the interval between each consecutive scan, was calculated. Bivariate and multivariate linear regression analyses were conducted to identify and evaluate the factors contributing to muscle loss. ICU patients experienced an average PMA decline of 46.0%, with a reduction of 41.8% observed in COVID-19 patients and 48.2% in AP patients. Notably, the long-term daily PMA loss was significantly greater in COVID-19 patients (1.88%) compared to AP patients (0.98%; p < 0.001). Linear regression analysis identified disease entity (p < 0.001), length of hospitalization (p < 0.001), and obesity as significant contributors to daily muscle deterioration. Patients admitted to the ICU for COVID-19 and severe AP can experience extreme muscle decay, reaching up to 48.2%. While decay rates vary considerably, COVID-19 patients experienced nearly twice the daily muscle loss compared to AP patients. Key factors contributing to muscle decay included disease entity, hospitalization duration, and obesity. These findings highlight the distinct impact of the underlying disease on muscle deterioration and emphasize the heightened risk for obese patients and those undergoing extended hospitalization.