Background: The literature suggests an association of pancreatic enzymes with systemic inflammation resulting in secondary organ injury and dysfunction following trauma. Elevation in serum enzymes may not always be predictive of pancreatic disease, and can reflect extra pancreatic production. Objectives: This study was conducted to evaluate the rise in serum pancreatic enzyme levels with the incidence of organ failure following trauma. Patients and Methods: A retrospective review was performed on critically injured patients from December 2009 to March 2010. Patient’s clinical demographics, routine laboratory investigations along with amylase and lipase levels were also extracted from the patients’ records. Patients with pancreatic or duodenal injuries were excluded from the study. Results: From a total of 296 patients (mean age, 31 years), 85% were males. Blunt injury was seen in 91.6% of the cases and 8.4% had penetrating injury. One hundred and fifty-three patients had single organ failure, 96 had multiple organ failure and 47 had no organ failure. There was a significant difference in lipase levels (P = 0.04), potassium levels (P = 0.05) and hemoglobin levels (P = -0.004), among the three patient groups. There was no significant difference in amylase levels among the three patient groups. The observed independent predictors of mortality included coagulopathy (OR = 1.7), Glasgow coma scale (OR = 1.1, 4.7), pulmonary failure (OR = 0.0004), hepatic failure (OR = 0.048), renal failure (OR = 5.5), organ failure (OR =149.8), lipase levels (OR = 1.3), and infection (OR = 3.0). Conclusions: There was a significant correlation between elevated lipase levels and the incidence of multiple organ failure. Moreover, No significant association was found between the elevated amylase levels and organ failure. However, on admission, measurement of these enzymes coupled with routine laboratory investigations can be a powerful tool in the early detection of patients progressing towards organ failure.