Background and Objectives: The aim of this systematic review was to examine the effect of 2% chlorhexidine following acid etching on the microtensile bond strength of resin restorations for different follow-up times. Materials and Methods: A thorough search of PubMed, Scopus, and Embase databases were conducted. In vitro experimental studies or in vivo studies published up to December 2018 with an experimental group treated with a 2% chlorhexidine solution following acid etching and a control group were included, wherein the final restoration used a resin composite in both the groups. Results: Twenty-one articles were identified for qualitative analysis and 18 for meta-analysis. The difference in the means of microtensile bond strength between the two groups was calculated for the different follow-up times. The differences were significant for 6 months (4.30 MPa; 95% CI 2.72–5.89), 12 months (8.41 MPa; 95% CI 4.93–11.88), and 2–5 years including aged and thermocycling samples (9.08 MPa; 95% CI 5.36–12.81). There were no significant differences for the type of adhesive used. A meta-regression model showed a significant effect of time on the microtensile bond strength. Conclusions: The application of a 2% chlorhexidine solution after acid etching increased the microtensile bond strength significantly for follow-up times of 6 months or more. The adhesive type had no influence.