Background: Rotavirus (RV), which causes RV-associated gastroenteritis (RVGE), has accounted for considerable morbidity. We aimed to assess the eﬀectiveness (VE) of the oral pentavalent RV vaccine (RotaTeq™) in real-world settings in children and infants with gastroenteritis. Methods: We performed a systematic search for peer-reviewed studies published between 1 January 2006 and 1 May 2020 and a meta-analysis to calculate the VE of RotaTeq™ vaccine. The primary outcome was the pooled three-dose vaccine VE. Stratified analysis of the vaccine VEs was performed according to dosages, study design, population age, socioeconomic status (SES), introduction condition, control group types, outcomes of RV disease, and RV strains. Results: After screening 2359 unique records, 28 studies were included and meta-analyzed. The overall VE estimate was 84% (95% confidence interval [CI], 80–87%). Stratified analyses revealed a nonnegligible impact of factors such as study design and SES. Other factors did not show great impart to VE with no significant differences between groups. Conclusions: RotaTeq™ is effective against RV infection, especially in high-income countries. Adopting suitable study methods and expansion of RV surveillance in low-income regions is crucial to assess VE in real-life settings and provide feasible vaccine regimens to improve vaccine VE.