Acute hypertriglyceridemic pancreatitis (HTGP) is more likely to be severe and complicated with extrapancreatic organ injury. NOX may be involved in the occurrence and development of high fat acute pancreatitis, but the specific mechanism is not clear. To investigate the protective effects of apocynin, an inhibitor of NOX, on kidney injury associated with the HTGP and its potential mechanisms in a rat model. In this study, HTGP rat model was induced by intraperitoneal injection of P-407 and L-Arg in combination. Apocynin was given by subcutaneously injection 30 min before the model was induced. The pancreatic and renal histopathology changes were analyzed. Serum AMY, BUN, Cr levels were measured by the Automatic Biochemistry Analyzer. The expression levels of protein associated with NOX/Akt pathway in the kidney were detected. ROS level in kidney and serum was measured by DHE staining and MDA, SOD kits, respectively. Serum TNF-α and IL-6 were detected by ELISA kits. In HTGP group, the levels of serum AMY, BUN, Cr, TNF- α, and IL-6 were significantly increased, and the injury of pancreas and kidney was aggravated. The levels of NOX4, NOX2, ROS, p-Akt, GSK-3β, NF-κB, and TNF-α in the kidney were detected, suggesting that NOX may regulate the activity of downstream p-Akt and GSK-3β by regulating ROS levels, thereby affecting the release of inflammatory mediators and regulating HTGP-related kidney injury. After application of apocynin, the expression of NOX4 and NOX2 and the level of ROS in the kidney were reduced, the release of inflammatory mediators decreased, and the histopathology injury of pancreas and kidney was improved obviously. NOX may play an important role in HTGP-associated kidney injury through Akt/GSK-3β pathway. Apocynin can significantly downregulate the level of NOX and play a protective role in HTGP-related kidney injury through Akt/GSK-3β pathway.