Objectives: This study was conducted to assess the therapeutic benefit of using rifaximin in combination with lactulose vs lactulose alone in the management of overt hepatic encephalopathy (OHE) within a tertiary care setting. Methods: A randomized controlled trial was conducted with 132 adult patients diagnosed with decompensated liver cirrhosis and presenting with OHE of West Haven Criteria grade II or higher. Participants were randomly allocated to receive either combination therapy (CT), comprising rifaximin and lactulose, or lactulose monotherapy (LM). Clinical outcomes were monitored over a 10-day period or until symptom resolution. The key outcome measure was symptom resolution in OHE, defined by reduction in grade and resolution of neurocognitive deficits. Results: Clinical improvement was achieved in 80.3% (n = 53) of patients receiving CT compared with 56.1% (n = 37) in the LM (p = 0.005). Response rates were significantly higher among males (82.5 vs 57.9%, p = 0.0329) and in patients aged 41–50 (85.7 vs 28.6%, p = 0.0308), 51–60 (78.1 vs 54.3%, p = 0.0401), and over 61 years (83.3 vs 54.5%, p = 0.0340) in the CT group compared with the LM group. Conclusion: The addition of rifaximin to standard lactulose therapy significantly improved clinical outcomes in patients with OHE, particularly among male patients and those in older age-groups, reinforcing its role as a preferred treatment strategy for OHE.