<p>Bone loss, linked with numerous oral conditions such as periodontal diseases and periimplantitis, poses a significant challenge for dental clinicians. The current study evaluated the in vivo effects of local application of Resolvin E1 (RvE1) on bone regeneration in critical size calvarial defects in rats. Thirty female Wistar rats with 5 mm induced calvarial defects were randomly allocated into four groups: no treatment (negative control, <i>n</i> = 5), treatment using bovine bone grafts (positive control, <i>n</i> = 5), treatment using local delivery of RvE1 (<i>n</i> = 11) and treatment using RvE1 mixed with bovine bone graft (<i>n</i> = 9). After 12 weeks, the animals were sacrificed and the calvarial defects with the adjacent tissues were sectioned en-bloc and prepared for histological examination. A comprehensive qualitative and quantitative histological examination was performed to assess bone regeneration and its relation to the defect, the presence of remnant bone and RvE1 particles, the integration of the native bone with the newly formed bone, bone density and bony trabeculae, the inflammatory reaction, the connective tissue bridging in the defect, and the encapsulating fibrous tissue. Signs of neovascularization, increased cellularity, lack of the organized lamellated appearance of mature bone, disorganized arrangement of osteocytes, osteoblasts and osteoclasts were also assessed. Comparisons of the quantitative values between all studied groups indicated statistically significant differences (<i>p</i> ≤ 0.05) in all parameters except for the increased cellularity and granulation tissue. Histological findings indicate that RvE1 with adjunct bone graft significantly enhanced the bone formation compared to RvE1 or bovine graft alone.</p>