Acute liver injury, a life-threatening condition, is characterized by oxidative stress, inflammation, and apoptosis with limited effective interventions. This study aimed to investigate the potential use of Sacubitril/valsartan (SAC/VAL) in lipopolysaccharide (LPS)-induced acute liver injury. Methods Thirty six adult male albino rats were allocated to 3 groups; control groups received either vehicles or SAC/VAL, LPS group received LPS (10 mg/kg, ip) and LPS+SAC/VAL group received LPS and 3 hours later received SAC/VAL (68 mg/kg, oral). Rats were sacrificed 6 hours following LPS injection. Results Rats from LPS group had higher serum tumour necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and liver enzymes (ALT and AST), but lower total antioxidant capacity (TAC) than control groups. Histological examination revealed distorted hepatocytes, congested blood vessels, periportal inflammatory cellular infiltration and increased liver injury score in LPS group compared to control group. Ultrastructurally, hepatocytes from LPS group had heterochromatic nuclei with vacuolated cytoplasm, swollen mitochondria and phagosomes. Treatment with SAC/VAL significantly reversed inflammation and oxidative stress and decreased liver injury score. Moreover, hepatocytes from LPS+SAC/VAL group had euchromatic nuclei with intact nucleoplasm. Immunohistochemical evaluation revealed obvious increases in the expression (number of immunopositive cells/field) of Toll-like receptor-4 (TLR-4) and nuclear factor-kappa B (NF-κB) and increased immunoexpression of pyroptotic inflammasome mediators, namely NOD-like receptor protein 3 (NLRP3), caspase-1 (Cas- 1) and interleukin-1 beta (IL-1β) in LPS group. SAC/VAL treatment, however reduced these increments. Conclusion, SAC/VAL can hinder sepsis-associated acute liver injury by inhibiting inflammation, oxidative stress, mitochondrial distortion, Kupffer cell hyperactivity and cellular pyroptosis.