Head and neck cancers are a significant global health burden, with radiation therapy being a frequently utilized treatment. The aim of this systematic review was to provide a critical appraisal of laboratory studies that assessed the effect of irradiation on the adhesive performance of resin-based biomaterials. The analysis included 23 laboratory studies obtained from five databases, with most studies using human enamel, dentin, or both, and bonding procedures involving the fabrication of direct restorations, standardized specimens, bonding of orthodontic brackets, and luting of endodontic fiber posts. The protocols used for irradiation varied, with most studies exposing specimens made from extracted teeth to irradiation using cabinet irradiators to simulate treatment of head and neck cancer. The findings indicate that irradiation reduces the bond strength of dental adhesives and resin-based composites on flat, ground enamel and dentin specimens, with different adhesives and timing of irradiation having a significant impact on adhesive performance. Irradiation also increased microleakage in most studies. The effect of irradiation on marginal adaptation of direct resin-based composite restorations was inconclusive. This systematic review indicates that irradiation has detrimental effects on the adhesive performance of resin-based biomaterials and highlights the need for further clinical and laboratory studies evaluating the performance of adhesive materials and approaches to improve it.