Background: Acute cholecystitis is one of the most common acute diseases of the biliary system and a frequent reason for emergency hospital admission and surgical treatment. More severe forms are associated with a higher need for intensive care, more frequent use of open surgery, and less favourable outcomes. Age and chronic comorbidity burden may play an important role in determining disease severity. The age-adjusted Charlson Comorbidity Index (CCI-Age) is a simple and widely used tool for integrated assessment of age and comorbidity burden, but its role in acute cholecystitis is not sufficiently defined. Methods: Data for this study were collected by retrospective analysis of hospital records from the hospital information system of the University Hospital Centre Zagreb. Patients treated conservatively were excluded. The association of age and CCI-Age with the severity of the clinical presentation of acute cholecystitis was analysed using dichotomised clinical variables and comparative statistical methods. Results: The results showed that age and the presence of chronic diseases were strongly associated with the severity of the clinical presentation of acute cholecystitis. Older patients and those with a greater burden of chronic comorbidities significantly more often developed more severe forms of the disease. Among chronic diseases, peripheral vascular disease, diabetes mellitus, and chronic renal disease showed the strongest association with more severe clinical presentation. Conclusions: Age and CCI-Age were strongly associated with the severity of the clinical presentation of acute cholecystitis. CCI-Age may represent a useful tool for early clinical risk stratification and support therapeutic decision making in everyday surgical practice.