Caries is a global health problem, and its prevention has become a main goal of modern dentistry. Laser irradiation is believed to have potential in preventing dental caries. The purpose of this systematic review and meta-analysis was to evaluate whether Er:YAG laser irradiation has the potential to prevent enamel caries. Based on inclusion and exclusion criteria, PubMed, Web of Science, and EMBASE databases were searched; 2 reviewers independently used these search strategies to review titles and abstracts, with no language or date restrictions, up to June 2023. For the quantitative analysis, continuous variables were analysed by standard mean difference (SMD) with a 95% confidence interval (CI). The statistical analyses were conducted using Review Manager and Cochrane Collaboration (2020). A total of 51 potentially eligible studies were identified, of which 16 in vitro studies were eventually included in the quantitative meta-analysis. Three studies showed a low risk of bias, and 13 studies a medium risk of bias. In general, there was no significant difference between the calcium ions released under acidic conditions after laser irradiation. The final results indicated that after Er:YAG laser irradiation, enamel could maintain higher surface microhardness in acidic environments, as well as smaller lesion depth and less mineral loss, revealing its potential in preventing enamel caries. However, the effect of laser irradiation on the release of calcium ions in acidic solutions and the surface microhardness of demineralised enamel was not significant. Therefore, more in vitro and clinical trials are needed in to evaluate whether Er:YAG laser irradiation can effectively prevent enamel caries in clinical settings.