Background: Multidrug-resistant (MDR) hospital-acquired infections (HAIs) have become a major global healthcare challenge, resulting in increased morbidity, mortality, prolonged hospitalization, and healthcare expenditure. Understanding the risk factors associated with MDR infections is essential for effective prevention and antimicrobial stewardship.Objective: To identify the clinical and demographic risk factors associated with multidrug-resistant hospital-acquired infections among hospitalized adult patients.Methods: A hospital-based observational cross-sectional study was conducted among 220 patients diagnosed with hospital-acquired infections after 48 hours of admission. Clinical characteristics, invasive procedures, antibiotic exposure, microbiological findings, and outcomes were analyzed. Data were analyzed using SPSS version 26.Results: The mean patient age was 54.2 ± 16.1 years, and males accounted for 59.1% of participants. The most common infection was hospital-acquired pneumonia (34.1%), followed by urinary tract infection (25.5%) and bloodstream infection (19.1%). MDR organisms were isolated in 132 patients (60.0%). Previous antibiotic exposure (72.7%), ICU admission (59.8%), mechanical ventilation (48.5%), central venous catheterization (43.2%), prolonged hospitalization (>10 days) (68.2%), diabetes mellitus (37.1%), and chronic kidney disease (18.2%) were significantly associated with MDR infections.Conclusion: Previous antibiotic use, prolonged hospital stay, ICU admission, invasive procedures, and underlying comorbidities significantly increase the risk of multidrug-resistant hospital-acquired infections. Early identification of high-risk patients and implementation of infection control measures can substantially reduce MDR infections.