Acute liver hepatotoxicity, characterised by inflammation, apoptosis and metabolic dysfunction, is often caused by drug-induced toxic events. This study evaluated the protective effects of COG133, a synthetic peptide derived from apolipoprotein E (ApoE), against carbon tetrachloride (CCl)-induced liver damage, focusing on inflammation, apoptosis and sphingolipid metabolism. An acute hepatotoxicity model was established in rats utilising CCl, with co-administration of COG133 at varying doses. Histological analyses, immunostaining, messenger RNA (mRNA)/protein quantification, flow cytometry and mass spectrometry were employed to assess necroinflammation, apoptosis and sphingolipid levels. Cell viability assays and morphological evaluations were conducted on rat hepatocytes and hepatic stellate cells (HSC-T6) to evaluate the protective effects of COG133. COG133 reduced liver damage, necroinflammation and apoptosis, restoring cell viability and lowering markers of inflammation, fibrosis and oxidative stress, including tumour necrosis factor-alpha (TNF-α), nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (NOS2), interleukin-1 beta (IL-1β), transforming growth factor-beta (TGF-β) and collagen type I (Col-1). Immunostaining and molecular analyses confirmed these effects. Sphingomyelin (SM) and sphingosine-1-phosphate (S1P) levels were partially restored, while ceramide (CER) levels remained reduced in COG133-treated groups. COG133 protects against CCl-induced liver injury by reducing inflammation, apoptosis and morphological damage, with partial restoration of sphingolipid metabolism. These findings support its potential as a novel therapeutic agent for acute liver injury.