This study systematically reviewed the literature to compare the bonding ability of dental adhesives applied to sound dentin (SoD) vs caries-affected dentin (CAD). Three international databases (Medline/PubMed, Scopus, and Web of Science) were searched. Eligible studies which evaluated the bond strength to both SoD and CAD were included. Random effects meta-analyses were conducted to calculate pooled mean difference between substrates, separately for etch-and-rinse and self-etch adhesives. Subgroup analyses were carried out to explore heterogeneity considering the methods used for removal of infected carious dentin. A comparison between etch-and-rinse and self-etch adhesives restricted to CAD was also performed. Statistical heterogeneity was considered using the I2 test. The risk of bias of all included studies was assessed. In total, 2260 articles were found, 65 were selected for full-text reading, and 40 studies were included. The meta-analyses favored SoD over CAD for both etch-and-rinse (effect size: -10.04; 95% confidence interval [CI]: -11.94, -8.14; I2 = 95%) and self-etch adhesives (effect size: -6.76; 95% CI: -8.23, -5.30; I2 = 89%). In the subgroup analyses, SoD was favored irrespective of the method used for caries removal (effect size ≤ -4.86; I2 ≥ 28%): excavation (manual or with burs), grinding with abrasive papers, combination of more than one method, and when the method was not mentioned. The meta-analysis restricted to CAD favored etch-and-rinse over self-etch adhesives (effect size: 3.13; 95% CI: 1.82, 4.44; I2 = 72%). Most included studies were judged as having an unclear risk of bias. Bonding to SoD yields better results compared to CAD. Etch-and-rinse adhesives performed better than self-etch adhesives when applied to CAD.