Macroamylasemia is a rare condition characterized by the formation of an amylase–globulin complex that is too large to be readily excreted by the kidneys and leads to elevated serum amylase levels. It is a benign condition lacking severe signs and symptoms that does not require treatment. This paper presents a case of a middle-aged man with unexplained elevated serum amylase levels. Despite an initially elevated triglyceride level, clinical findings, laboratory test results, and radiological findings were not suggestive of pancreatitis. The ratio of renal amylase clearance to creatinine clearance was calculated at <1%, consistent with macroamylasemia. No specific treatment was given, and he was monitored periodically. Nevertheless, macroamylasemia is a diagnostic challenge because of the need to differentiate it from other causes of hyperamylasemia to avoid unnecessary tests and treatments.