Background: Nowadays, most of the dental manufacturers claimed that ‘Universal’ or ‘multi-mode’ adhesives in self-etch technique can obtain good bonding results comparing to etch-and-rinse or selective etching application techniques. The rationale behind this study was that a multi-mode adhesive, when proven to be effective, would enable general practitioners to apply the adhesive using either an ‘etch-and-rinse’ or an ‘self-etch’ adhesive mode strategy, basically depending on their interpretation of what appears to be most appropriate upon examination of the actual cavity and the overall restoration conditions. Objective: This study examined the effect of acid etching on microtensile bond strength (μTBS), micromorphological patterns of resin-dentin interface using scanning electron microscope (SEM) and SEM of tracer-infused water-rich zones within the hybrid layers of ultra-mild self-etch adhesives bonded to coronal dentin. Methods: Sixty extracted permanent molars were assigned into six groups based on μTBS (n = 10). The groups were bonded with Adper single bond (SB) plus adhesive in etch-and-rinse mode and Adper easy one (EO) bond in self-etch mode as controls; Single Bond Universal self-etch (SUSe) and etch-and-rinse (SUEr); Adhese Universal self-etch (AUSe) and etch-and-rinse (AUEr). The bonded specimens were stored in deionized water for 24 h. Composite/dentin beams were prepared (1 mm2). μTBS testing was performed. Micromorphological evaluation of extra teeth from each study group was conducted using SEM, and nanoleakage (NL) was evaluated. μTBS data were statistically analyzed using two-way ANOVA and multiple comparison post-hoc tests. Results: AUEr had the highest μTBS (p < 0.05). There was a significant difference in μTBS between AUEr and AUSe (p < 0.05). No significant difference was found in μTBS between SUSe and SUEr (p > 0.05). The μTBS for SUEr was similar to the SB control adhesive (p > 0.05), while the μTBS for SUSe was higher than the EO control adhesive (p < 0.05). A comparison of both materials showed that the μTBS was significantly higher for AUEr than SBEr (p < 0.05). The thickness of the hybrid layers created by these adhesives in the etch-and-rinse mode and the self-etch mode were approximately ~5 mm and ≤0.5 mm, respectively. Silver nitrate infused regions were identified within the resin-dentin interface in all the bonded specimens. Conclusion: Application of an etching step prior to water-based adhesive improves its dentin penetration, but it does not affect its μTBS; while application of an etching step prior to ethanol-based adhesive improves its dentin penetration and its μTBS.