Although there are several studies that have evaluated the bond strength of various adhesives to healthy dentin and caries-affected dentin after traditional caries removal, the objective of this systematic review aimed to assess the bond strength of various adhesives to caries-affected dentin (CAD) after chemo-mechanical caries removal (CMCR) treatment. The review adhered to PROSPERO protocol registration and followed PRISMA guidelines. The research question focused on the bonding effectiveness of dental adhesives to CAD after employing the chemo-mechanical caries removal method. PubMed, the TRIP database, and Scopus were searched, with the last search conducted in February 2023. Two reviewers independently screened and evaluated articles, resulting in 30 articles for full-text analysis out of 434 retrieved from databases. Twelve eligible studies were included in the review. The bond strength of etch-and-rinse (ER) and self-etch (SE) adhesive systems was assessed following CMCR treatment on CAD. SE adhesive systems exhibited higher bond strength to CAD compared to ER adhesive systems. Meta-analysis indicated that the bond strength achieved with self-etching adhesive systems remained consistent, regardless of the CMCR agent (Carisolv or Papacarie) used on dentin. The findings of this systematic review suggest that self-etch adhesive systems show favorable bond strength to caries-affected dentin following chemo-mechanical caries removal, regardless of the specific CMCR agent used. These results support the use of minimally invasive dentistry techniques aimed at preserving healthy tooth structure, dentin in particular.