Background: Polymerization shrinkage of composite resins affects the marginal closure of direct dental restorations. It is responsible for developing secondary caries and indirectly affects the survival rate of restorations. This study aims to investigate the null hypothesis, which states that there are no significant differences in the marginal microleakage of Class II restorations when examined in vitro using different dental adhesives, whether the restoration material used is a composite with glass fiber reinforcement or not. Methods: Class II cavities were prepared on both proximal surfaces of thirty-six extracted human molars. A single-component (Universal VivaPen) and a two-component (Futurabond DC) self-etch adhesive system were used for the restorations in the control group (Charisma Classic) and the experimental group (Charisma Classic with Interlig glass fiber strip). An oblique layering technique and a 40-s soft-start light-curing polymerization were used. After selective pre-isolation, the specimens were placed in a 0.2% methylene blue solution and incubated at 37 °C for 24 h. The teeth were sectioned in the mesiodistal direction, and two examiners examined and graded the extent of dye penetration. Statistical analysis was conducted using the Mann–Whitney U and chi-square tests (p < 0.05). Results: All the composite restorations reinforced with glass fiber showed significantly reduced dye infiltration compared to the control group (p < 0.05). A significant difference (p < 0.05) was also observed between the two adhesives. Conclusions: The null hypothesis was rejected. Glass fiber strips significantly reduced composite restoration microleakage regardless of the adhesive. The marginal fit of the restoration was also influenced by the adhesive system used.