Introduction Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disease worldwide, particularly in South Asian countries like Pakistan. Gallstone disease (GSD), often associated with metabolic abnormalities, shares several risk factors with MAFLD, such as obesity, diabetes, and dyslipidemia. Despite international evidence supporting an association between MAFLD and GSD, there is a hdlscarcity of local data in this regard. Therefore, this study aimed to determine the independent predictors of GSD in MAFLD patients in Pakistan. Study methodology This cross-sectional study was conducted at the Hepatogastroenterology Department of Sindh Institute of Urology and Transplantation (SIUT) from January to December 2024. A total of 350 adults with the presence of fatty liver on ultrasound were enrolled. Patients with significant alcohol intake, those with known liver diseases, prior cholecystectomy, pregnancy, and use of lipid-altering medications were excluded from the study. Demographic, clinical, and laboratory parameters were recorded. Gallbladder stones were identified using abdominal ultrasound. Univariate analysis followed by multivariate logistic regression was performed to identify the independent predictors of GSD. Results Among 350 patients with MAFLD, 102 (29.1%) had gallstones. Patients with gallstones were significantly older (mean age 52.1 vs. 47.1 years, p<0.001), with a higher prevalence of female gender (63.7% vs. 35.4%, p<0.001) and diabetes mellitus (68.6% vs. 48.3%, p = 0.002). Laboratory markers including alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total cholesterol, triglycerides, and fasting blood sugar (FBS) were significantly elevated in the gallstone group, whereas high-density lipoprotein (HDL) was significantly lower. Multivariate logistic regression identified increasing age (OR 1.04), female gender (OR 2.73), diabetes mellitus (OR 1.89), elevated ALP (OR 1.02), low HDL (OR 1.76), and elevated FBS (OR 1.31) as independent predictors of gallstones in MAFLD. Conclusion In this study, 29.1% of MAFLD patients had GSD. Older age, female gender, diabetes, elevated ALP, low HDL, and high FBS were the factors independently associated with the presence of GSD in MAFLD. Further multi-centered prospective studies incorporating dietary, hormonal, and genetic factors are required for the validation of these results.