Objectives <p>ROTASIIL^®, an indigenous oral pentavalent rotavirus vaccine, was included in the Universal Immunization Program of Kerala in September 2019. This study aimed to describe the epidemiology and clinical profile of rotavirus diarrhea among children aged under 5 y in Kerala in the postvaccination period.</p> Methods <p>This prospective observational study was conducted at three tertiary-care hospitals in Kerala from November 2020 to December 2023. Children aged under 5 y who were hospitalized with acute diarrhea were enrolled. Stool samples were collected from participants and tested for rotavirus using an enzyme-linked immunosorbent assay. Rotavirus-positive samples were genotyped.</p> Results <p>Of the 666 children enrolled, 643 had a stool sample tested for rotavirus, of which 17.9% tested positive. Rotavirus diarrhea occurred throughout the year, with a small peak between December and February. Most children with acute rotavirus diarrhea (56.5%) were aged 24–59 mo. The incidence of rotavirus-positive and rotavirus-negative acute diarrhea was higher among boys than among girls (male-to-female ratio of 1.3:1 and 1.5:1, respectively). The prevalence of rotavirus positivity was lower in children who had received three doses of oral rotavirus vaccine, ROTASIIL^® than in unvaccinated children (13.9% vs. 26.4%). G3P[8] was the dominant rotavirus genotype throughout the study period. No fatal cases of rotavirus diarrhea were reported.</p> Conclusions <p>In children hospitalized with acute diarrhea, the prevalence of rotavirus was lesser among vaccinated than unvaccinated children. Monitoring of age shift, breakthrough infections in vaccinated children, and genotypic surveillance of emerging rotavirus genotypes are required to inform the development of next-generation vaccines.</p>