To compare the effectiveness of hydrophilic resin-based versus hydrophobic resin-based and glass-ionomer pit and fissure sealants. The review was registered with Joanna Briggs Institute and followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed, Google Scholar, Virtual Health Library, and Cochrane Central Register of Controlled Trials were searched from 2009-2019 using appropriate keywords. We included randomized controlled trials and randomized split-mouth trials conducted among 6-13-year-old children. The quality of included trials was assessed using modified Jadad criteria and risk of bias using guidelines specified by Cochrane. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines were used to assess the overall quality of studies. We used the random-effects model for meta-analysis. Relative risk (RR) and confidence intervals (CI) were calculated & heterogeneity was tested using I² statistic. Six randomized clinical trials and five split-mouth trials met the inclusion criteria. The outlier augmenting the heterogeneity was omitted. Based on very-low to low-quality evidence, loss of hydrophilic resin-based sealants was less likely as compared to glass-ionomer fissure sealants (4 trials at 6 months; RR = 0.59; CI = 0.40-0.86), while it was similar or slightly lower than hydrophobic resin-based sealants (6 trials at 6 months; RR = 0.96; CI = 0.89-1.03); (6 trials at 12 months; RR = 0.79; CI = 0.70-0.89); (2 trials at 18 months; RR = 0.77; CI = 0.48-0.25). This study revealed that retention of hydrophilic resin-based sealants is better than glass ionomer sealants but similar to hydrophobic resin-based sealants. However, higher-quality evidence is necessary to underpin the outcomes.