Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-κB-dependent inflammation has been overlooked. Cysteine cathepsins (Cathepsin B or S, CTSB/S) execute specific functions in physiological processes, such as protein degradation, having SIRT1 as a substrate. We investigated the roles of CTSB/S and SIRT1 in the regulation of hepatic inflammation using primary parenchymal and non-parenchymal hepatic cell types and cell lines. In all cells analyzed, CTSB/S inhibition reduces nuclear p65-NF-κB and κB-dependent gene expression after LPS or TNF through enhanced SIRT1 expression. Accordingly, SIRT1 silencing was sufficient to enhance inflammatory gene expression. Importantly, in a dietary mouse model of non-alcoholic steatohepatitis, or in healthy and fibrotic mice after LPS challenge, cathepsins as well as NF-κB-dependent gene expression are activated. Consistent with the prominent role of cathepsin/SIRT1, cysteine cathepsin inhibition limits NF-κB-dependent hepatic inflammation through the regulation of SIRT1 in all in vivo settings, providing a novel anti-inflammatory therapeutic target in liver disease.