Background: This study aimed to evaluate the effects of lycopene gel, as a natural antioxidant, mixed with a nanohydroxyapatite graft (NHG) covered by an occlusive resorbable collagen membrane (CM) in the surgical treatment of grade II furcation defects and on the gingival crevicular fluid (GCF) levels of 8-hydroxydeoxyguanosine (8-OHdG), as a marker of oxidative injury. Methods: In this randomized controlled clinical study a total of 24 patients with grade II furcation defects were randomly assigned into three equal groups. Furcation defects in group I were managed with lycopene gel mixed with NHG and CM, group II with NHG and CM, and group III with open flap debridement only. Site-specific changes in clinical parameters including probing depth (PD), vertical clinical attachment level (VCAL), horizontal clinical attachment level (HCAL), radiographic maximum vertical depth (MAX V), and maximum horizontal depth (MAX H) were measured at baseline and six months postoperatively. Gingival crevicular fluid levels of 8-OHdG were analyzed using enzyme-linked immunosorbent assay (ELISA) at baseline, one week, and three months. Results: Surgical management of grade II furcation defects resulted in a significant reduction in PD and 8-OHdG levels and a gain in CAL, MAX V, and MAX H in all groups. The differences between lycopene treated sites compared to NHG and CM alone were not significant at six months but demonstrated significantly superior clinical parameters compared to open flap debridement alone. Conclusion: Lycopene does not confer a benefit when combined with NHG in the surgical treatment of grade II furcation defects.