Objectives Cholelithiasis poses a considerable medical burden worldwide. While its pathogenesis is multifactorial, identifying the key risk factors is essential for understanding the disease and improving patient care. This study aims to investigate the potential associations between demographic, clinical, and laboratory variables and the development of cholelithiasis. Methods This single-center retrospective study was conducted at Malla Reddy Institute of Medical Sciences, Hyderabad, India, over one month. A total of 200 patients diagnosed with cholelithiasis were included. Data were extracted from electronic health records and the patients using a questionnaire, including demographic information (age, gender), clinical data including body mass index (BMI), and comorbidities. Statistical analyses were conducted to determine the associations between risk factors and cholelithiasis. Results The frequency of cholelithiasis is found to be higher in the female gender and patients with obesity, sedentary lifestyle and hypertension as compared to male patients, and the risk of cholelithiasis also increases with age. Females demonstrated a higher prevalence of cholelithiasis, with an odds ratio (OR) and confidence interval (CI) of 1.4, 95% CI [1.1, 1.7], p < 0.05). Obese individuals (BMI ≥ 30) had 2.2 times higher odds of cholelithiasis compared to those with normal BMI (< 24.9) (OR = 2.2, 95% CI [1.7, 2.9], p < 0.001). The presence of diabetes significantly increased the odds of cholelithiasis by 1.6 times (OR = 1.6, 95% CI [1.2, 2.1], p < 0.01). Overweight individuals (BMI: 25-29.9) were associated with 1.4 times higher odds of cholelithiasis (OR = 1.4, 95% CI [1.1, 1.9], p < 0.05). Conclusion Our study identified age, gender, BMI, diabetes, and obesity as significant risk factors for cholelithiasis. These findings underscore the importance of targeted interventions and lifestyle modifications to mitigate cholelithiasis risk and improve patient outcomes. Further research, including prospective multicentric studies, must validate these findings and explore potential underlying mechanisms.