Hypercholesterolaemia is well known to be associated with mitochondrial dysfunction, subsequently leading to multiple organ failure. Similar to other natural products, sericin is a candidate for adjunctive therapy in hyperlipidaemic conditions. However, the cholesterol-lowering mechanisms of sericin are multifactorial and controversial. Here, a high-cholesterol-fed rat model with or without sericin treatment was established using a dosage of 1000 mg/kg/day for 30 days. Blood lipid profiles, oxidative stress markers (superoxide dismutase, SOD; malondialdehyde, MDA; nuclear factor erythroid 2-related factor, Nrf-2), dysmorphic mitochondria in relation to fission (dynamin-related protein-1; Drp-1) and fusion (guanosine triphosphatase mutated in dominant optic atrophy; OPA-1) markers and biosynthetic markers (aquaporin, AQP-1; tubulin-4β, Tb4B) in the pancreas and adrenal gland were evaluated. The results showed that sericin reduced blood cholesterol and increased high-density lipoprotein (HDL) by acting against oxidative stress. Hypocholesterolaemic and antioxidant conditions further preserved heart and liver mitochondrial architecture; however, this protection was not exhibited in the kidney, where a high level of renal mitophagy, indicating by LC-3 up-regulation, was presented. The steps of ultrastructural alteration of mitochondria from degenerative changes to necrosis were also demonstrated. Sericin also conserved AQP-1 and Tb4B levels in the exocrine pancreatic acinar cells and zona glomerulosa cells, which were positively correlated with serum lipase, HDL, antioxidative markers and mitochondrial integrity. The present study revealed that sericin not only has antioxidant capacity but also balances pancreatic and adrenal cell biosynthesis, especially lipase activity, which may have played an important role in improving lipid dysregulation in the hypercholesterolaemic rat model, leading to the reduction of dysmorphic mitochondria, particularly in the heart and liver.