Background: Angelica gigas Nakai (AGN) is well-known for anti-inflammatory and anti-oxidative effects; however, the mechanism underlying the protective effects of AGN on monosodium iodoacetate (MIA)-induced osteoarthritis (OA) remains unknown. Objectives: Our objectives of this study were to evaluate the anti-inflammatory effect of AGN on MIA-induced OA and investigate the potential mechanism which underlies such effect. Materials and Methods: The dried herb AGN was extracted with distilled water. After the experiment was conducted for 4 weeks using 7-week-old male Sprague–Dawley rat. AGN (200 mg/kg body weight/day) was orally administered for 14 days from day 7 after intra-articular injection of MIA (50 μL with 80 mg/mL), and the effects were compared with those of MIA-treated control group. We examined the weight-bearing ability of hind paws, biomarkers related to oxidative stress in cartilaginous tissue. In addition, various factors associated with inflammatory and cartilage degeneration in cartilaginous tissue detected by the Western blot analysis. Results: Our results from an in vivo model of OA indicate that AGN inhibits inflammatory factors such as inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1β via nuclear factor kappa B signaling pathway. AGN suppresses the expression of matrix metalloproteinase, proteolytic enzyme, and also elevates tissue inhibitor of metalloproteinase which inhibited degradation of the extracellular matrix. Moreover, antioxidant defense was enhanced through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Conclusion: Taken together, these results demonstrate the effectiveness of AGN at the inflammation associated with joint disorders. Our results also suggest that AGN could serve as a potential candidate for alternative therapeutic treatment of OA.