The human rabies immunoglobulin (HRIG) is a life-saving immune biological essential for all category III animal exposures. It provides neutralizing antibodies at the site of exposure until the body can produce vaccine-mediated antibodies. We conducted this study to determine the safety and clinical efficacy of an HRIG being used presently for post-exposure prophylaxis (PEP) and to strengthen the existing evidence for its further usage. We conducted a prospective cohort study in 123 subjects with category III animal exposures at the KIMS Hospital and Research Center, Bangalore, India. Post-exposure prophylaxis (PEP) with wound toilet, a single application of HRIG, and a full course of anti-rabies vaccination were provided to all the study subjects. The volume of HRIG was calculated according to the body weight, and all the wounds were infiltrated as was anatomically feasible. All the study subjects were followed up for immediate and delayed adverse events (AE), both local and systemic. Subsequently, all the subjects were followed up for 6 months to demonstrate the clinical efficacy of PEP. The incidence of AEs was 11.4% including local pain, erythema, itching, headache, body ache, fever, and malaise. All AEs were mild and subsided without any complications. All the study subjects were healthy and alive after 6 months following the administration of HRIG, along with a full course of anti-rabies vaccine. Our study provides evidence of safety and clinical efficacy of HRIG for category III animal exposures and supports its continued usage.