Severe trauma can result in secondary multiple organ dysfunction syndrome (MODS) and death. Inflammation response and oxidative stress promote the occurrence and development of MODS. TNFAIP3‑interacting protein 2 (TNIP2), which can repress the activation of nuclear factor‑κB (NF‑κB) and may be involved in MODS progression, has not been studied in regards to MODS. The present study aimed to investigate the expression, role and mechanism of TNIP2 in MODS following severe trauma. The expression level of TNIP2 was initially detected in the blood of patients with MODS using reverse transcription‑quantitative polymerase chain reaction and western blot assay. Then, to investigate the role of TNIP2 in MODS, a MODS rat model was conducted by trauma and the model rats were treated with TNIP2‑plasmid (intraperitoneal injection). Blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatine (Cr) and creatine kinase (CK); and tumor necrosis factor α (TNF‑α), high‑mobility group box 1 (HMGB‑1), malondialdehyde (MDA) and total antioxidant capacity (TAC) in the different groups were assessed. In addition, activation of NF‑κB was assessed by detecting the level of phospho‑p65. The results showed that TNIP2 was significantly decreased in the blood of patients with MODS. TNIP2 was also significantly downregulated in the blood and the pulmonary, renal and hepatic tissues of MODS rats. The levels of ALT, AST, LDH, BUN, Cr and CK were markedly increased in the blood of MODS rats, and these increases were inhibited by TNIP2‑plasmid administration. Moreover, blood levels of TNF‑α, HMGB‑1 and MDA were significantly increased in MODS rats, while TAC was notably decreased, and these changes were prevented by TNIP2‑plasmid administration. Furthermore, it was found that activation of NF‑κB induced by MODS was eliminated by TNIP2‑plasmid. In conclusion, the data indicated that TNIP2 is significantly decreased in MODS following severe trauma, and it plays a protective role in MODS development by inhibiting the inflammation response and oxidative stress by preventing NF‑κB activation.