Background: Antimicrobial resistance (AMR) is an increasing global problem that makes the treatment of infections with traditional antimicrobials less effective. The clinical efficacy and safety of ceftriaxone–sulbactam treatment was evaluated in hospitalized patients. Methods: A prospective observational hospital based study was done at Adesh Hospital, Bathinda with 113 adult inpatients on ceftriaxone–sulbactam therapy for a period of 3 months. Demographic, clinical, treatment, response, and adverse drug events (ADEs) were recorded. The data were analyzed by descriptive statistics and chi square test. Results: The majority of patients (68.1%) were treated for 3-7 days. The overall success rate for ceftriaxone–sulbactam therapy was 76.1% (highly effective), 20.4% (effective), and 3.5% (partial success). There was a significant association between the duration in treatment and effectiveness (p < 0.05). Of patients, 33.6% improved within 48–72 hours and 43.4% improved after 72 hours. During treatment, no patient needed further antibiotic treatment. The most common clinical indication was cholelithiasis (34.5%). Conclusion: In the hospitalized population, ceftriaxone–sulbactam was shown to be clinically effective and well tolerated, and experienced a low rate of mild ADEs. Further studies of larger size with microbiological and antimicrobial susceptibility data are warranted to confirm the findings and to provide a rational approach to antimicrobial use.