Abstract Aims and Objectives: Studies on resin infiltration and its penetration capability are becoming the focus of emerging dentistry. The depth of resin penetration could be a key determining factor in creating a diffusion barrier and in the success of infiltration. The aim of this review article was to evaluate the penetration depth of commercially available resin infiltration in early caries lesions and to identify factors that influence the penetration capability of resin infiltration. Materials and Methods: A literature search was performed in four databases (PubMed, Science Direct, Scopus, and Web of Science) and manual searching from 2009 to December 2022. Eligibility criteria included in vitro studies pertaining to factors affecting the penetration depth of resin infiltration into the enamel. The risk of bias assessment was done by using checklist for reporting in vitro studies (CRIS). Results: The initial search resulted in a total of 297 studies. Twenty-nine were assessed for eligibility, and 23 were selected in the qualitative synthesis. According to the CRIS guidelines, all of the studies were classified as moderate risk of bias. The penetration of resin infiltration is influenced by the enamel surface treatment with hydrochloric acid, formulations containing triethylene glycol dimethacrylate (TEGDMA), the addition of ethanol, penetration time, duration of penetration time, saliva contamination, caries activity, and type of tooth. The hypermineralized surface layer needs to be removed for better resin perfusion. Conclusion: The key to optimal resin infiltration depends on the enamel surface treatment with hydrochloric acid and application technique, infiltration duration, formulation of TEGDMA and ethanol in the resin composition, as well as the type and caries activity of involved teeth. Resin infiltration has superior penetrability compared to fissure sealant, casein phosphopeptide-amorphous calcium phosphate nanocomplexes, flowable composite, adhesive and fluoride varnish. Resin penetration depth may be a critical factor in forming a diffusion barrier and the effectiveness of infiltration in halting the progression of caries.