Background: Silymarin has intracellular antioxidant property and inhibits activation of nuclear factor-κB (NF-κB) in low concentrations and reduces tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 levels, cyclooxygenase (COX), and angiogenesis. Selenium is one of the necessary trace element nutrients for human and animals. Selenium nanoparticles (nano-Se) have more bioavailability with less toxicity. Aims: To investigate the combination effect of silymarin and nano-Se on inhibition of NF-κB, proinflammatory cytokines, and oxidative stress biomarkers in the experimental colitis. Methods: Trinitrobenzene sulfonic acid (TNBS) was used to induce colitis. After TNBS instillation, rats were distributed into six groups, containing silymarin and nano-Se alone or in combination, dexamethasone, negative control with no treatment and the last one was normal sham rats. All drugs were administered for 7 days. Colon samples were scored macroscopically and microscopically. The levels of activated NF-κB, IL-1β, TNF-α, myeloperoxidase (MPO), lipid peroxidation, protein carbonyl (PC), and the antioxidant power of the colon homogenates were determined. Result: A significant decrease in NF-κB activity in treated groups was observed. The levels of TNF-α, IL-1β, MPO, lipid peroxidation, and PC were reduced and an improvement in antioxidant power of treated groups was seen. Combination of silymarin and nano-Se were more effective than each one alone in improvement of NF-κB, TNF-α, antioxidant power, and lipid peroxidation values, although this difference was not significant in other factors. Conclusion: Co-administration of silymarin and nano-Se with a good antioxidant profile and inhibition of NF-κB is a possible candidate for better management of inflammatory bowel disease.