Ketosis is an important metabolic disease that can negatively affect the production efficiency of dairy cows. Earlier studies have revealed metabolic and inflammatory alterations in the blood associated with ketosis; however, a link between ketosis and hepatic inflammation has not been well documented. The objective of this study was to investigate whether the nuclear factor kappa B (NF-κB) signaling pathway and NLR family pyrin domain containing 3 (NLRP3) inflammasome were activated in the liver of ketotic cows. Liver and blood samples were collected from healthy (n = 15, control group) and ketotic (n = 15, ketosis group) cows that had a similar number of lactations (median = 3, range = 2 to 4) and days in milk (median = 6 d, range = 3 to 9 d). Results showed that serum levels of fatty acids, β-hydroxybutyrate (BHB), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were higher and glucose was lower in ketotic cows. Concentrations of serum proinflammatory cytokines IL18, tumor necrosis factor (TNF)-α, and IL1B were greater and the anti-inflammatory cytokine IL10 was lower in the ketosis group. Cows with ketosis had triacylglycerol accumulation in the liver. Upregulation of phosphorylated (p)-NF-κB and p-inhibitor of κB (IκB)α protein abundance in cows with ketosis indicated that the hepatic NF-κB signaling pathway was overactivated. The mRNA abundance of TNFA, inducible nitric oxide synthase (NOS2), IL18, and IL1B were greater and IL10 was lower in ketotic cows. More importantly, the mRNA and protein abundance of NLRP3 and caspase-1 (CASP1) along with CASP1 activity were greater in the liver of cows with ketosis. Overall, the data indicate that the onset of ketosis is accompanied by activation of the NF-κB signaling pathway and NLRP3 inflammasome, resulting in a state of inflammation.