Purpose: To analyze the effects of sustained-release polylactic-co-glycolic acid (PLGA)-coated melatonin microspheres on free radical injury and osteoblastic activity around dental implants. Materials and methods: Ten patients with bilateral missing posterior teeth were recruited as study participants. Twenty edentulous sites were randomly allotted to receive PLGA-encapsulated melatonin and placebo microspheres, followed by the placement of implants of dimension 3.75 × 11.5 mm. Free radical injury was assessed through the expression of the specific marker malondialdehyde (MDA) on the 15th day after implant placement. Osteoblastic activity was assessed using alkaline phosphatase (ALP) on the 30th and 90th days after implant placement. An independent t-test was used to compare the experimental and control groups. Intragroup comparison was performed by using repeated-measures ANOVA (α = 0.05). Results: The analysis of the independent t-test revealed that, on the 15th day of implant placement, MDA values were lower at the experimental sites (6.010 ng/mL) than at the control sites (9.080 ng/mL), which was statistically significant (p < 0.05), indicating lesser free radical injury with melatonin-coated microspheres. The mean osteoblastic activity was higher in the experimental group than in the control group on the 30th and 90th days after implant placement (p < 0.001). Conclusion: Locally administered sustained-release PLGA-coated melatonin microspheres reduced free radical injury around dental implants on the 15th day. ALP levels indicated improved osteoblastic activity until the 90th day. In addition to combating free radical injury, melatonin also has a positive influence on early implant healing through improved osteoblastic activity.