Introduction: The aim of this in vitro study was to compare the quality of marginal sealing at the cervical margins of indirect and direct composite resin restorations in mesio-occluso-distal (MOD) cavities. Material and method: MOD preparations were performed on 30 extracted teeth. The mesial cervical margin of each tooth was relocated using a flow composite resin (Enamel Plus HRi Flow, Micerium, Avegno, GE, Italy), then the samples were divided into three groups. In group A, the cavities were directly restored using a nanohybrid composite resin (Miris 2 Coltène Whaledent, Altstaetten, Switzerland) and a universal adhesive (ScotchBond Universal, 3M ESPE, St. Paul, MN, USA) by the etch-and-rinse strategy, for group B, the restoration procedure was similar but the self-etch strategy was used, and the samples in group C were filled using the inlay technique. Each sample was stored for 48 h in a 2% methylene blue solution, then it was cut in a mesio-distal direction using a Struers Secotom 50 device (Cleveland, OH, USA). The marginal sealing and adhesive interface were assessed for each sample at the cervical margin by optical microscopy (OM) and scanning electron microscopy (SEM). One-way ANOVA and Bonferroni post-hoc tests were used with a significance level of 0.05. Results: Significant differences were recorded within groups A and C, between mesial and distal margins (p = 0.02 in group A and p = 0.043 in group C). Conclusions: The marginal sealing is more effective in MOD inlay restoration compared to direct restorations. Relocation of the cervical margin with flow composite resin and the use of different adhesive strategies do not improve the marginal sealing.