Objective Self-etching dental adhesives bond with dentin through chemical reactions with calcium. This study assessed bond strength (BS) using microtensile (mu TBS) and microshear (mu SBS) tests on sound and post-radiotherapy dentin, with dental adhesives containing different functional monomers. Methods Sound dentin (SD) and post-radiotherapy irradiated dentin (ID) were tested with two adhesive systems: Clearfil SE Bond (SE, 10-MDP-based) and FL Bond II (FL, containing carboxylic and phosphonic monomers with S-PRG bioactive particles). The tests occurred initially (24 h) and six months later; fracture mode was also analyzed (40x). Ninety-six human molars were randomly assigned (n = 12), and half were irradiated with a 70 Gy radiation dose. For mu TBS test, teeth were bonded, restored and sectioned them into beams (0.64 mm(2)). The mu SBS test used filled transparent cylindrical matrices with resin composite and light-cured them after dental adhesive applications. Three-way ANOVA and Tukey's test (p < 0.05) analyzed the data. Results <mu>TBS showed a significant substrate x adhesive interaction (p < 0.001), while <mu>SBS was significant for all factors (p = 0.006). SE and FL performed better on SD and ID, respectively, in the mu TBS test. As for mu SBS, SE showed higher values on ID (p < 0.05). Lower BS values occurred for SD-FL and ID-SE after six months. Conclusion Dental adhesive performance varied based on substrate type and test method. FL was more stable for ID in <mu>TBS, while SE excelled in mu SBS. Clinical relevance As post-radiotherapy irradiated dentin becomes more vulnerable, self-etching systems based on functional monomer and bioactive ingredients may exhibit appropriate bonding to this altered substrate.