Abstract Background The objective of this clinical study was to assess the potential benefit of a dietary supplement, NP 06-1, on joint health in overweight and normal weight adults diagnosed with osteoarthritis. Methods An 8-week placebo-controlled, randomized, double-blind study was conducted with four groups comparing the effects of NP 06-1 to placebo on overweight and normal weight subjects diagnosed with primary osteoarthritis of the knee. NP 06-1 (a combination of two botanical extracts; Phellodendron amurense bark and Citrus sinensis peel) or matching placebo were given in a dose of two capsules (370 mg each) twice daily. The outcome measures were the Lequesne Algofunctional Index (LAI) for joint pain and movement as well as biomarkers of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]). Results Eighty (80) subjects were enrolled and 45 subjects completed the study. No serious adverse events were reported. The mean total LAI scores at baseline for the four groups ranged from 11.4 to 12.4 (SD 1.2 to 2.4). Treatment for 8 weeks resulted in a statistical improvement in the LAI score in the overweight treatment group compared to placebo (6.3 ± 2.3 vs 11.8 ± 1.5; p < 0.0001). At 8 weeks, a similar result was observed in the normal weight groups (7.7 ± 1.4 vs 9.9 ± 0.9; p < 0.0001). There was a reduction in CRP levels with treatment in the overweight treatment group at 8 weeks (-0.62 ± 0.2; 49%) compared to baseline (p < 0.001) and to placebo (p < 0.001). For the normal weight participants, there were significant reductions in CRP compared to baseline, but not to the matched placebo group. Both overweight and normal weight treatment groups lost a significant amount of weight compared to their placebo groups. The overweight treatment group lost an average of 5% body weight after 8 weeks. There was no significant change in ESR in any of the groups. Conclusion In this pilot study, NP 06-1 had beneficial effects on symptoms of osteoarthritis of the knee as measured using LAI scores and had anti-inflammatory effects as measured using CRP. Administration of NP 06-1 was also associated with weight loss, which may have been a contributing factor to the other benefits.