We recently identified that a serine/threonine kinase, p21-activated kinase 4 (PAK4), plays a key role in liver lipid metabolism. However, whether PAK4, specifically in myeloid cells, is involved in the progression of metabolic dysfunction-associated steatohepatitis (MASH) has not been investigated. We generated myeloid-specific Pak4 knockout (KO) mice by crossing Pak4 floxed mice with LysM-Cre recombinase mice and fed them a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 12 weeks. Hepatic fat accumulation, inflammation, and fibrosis were compared with those in wild-type mice. Body weight increase for this period were less in Pak4 KO mice than in WT mice. CDAHFD feeding induced hepatic steatosis as demonstrated by liver triglyceride content, Oil Red O staining, and lipogenic gene expressions. Pak4 KO mice also showed reduced inflammation and attenuated fibrosis. Specifically, hepatic infiltration of F4/80-positive cells and serum TNF-α levels were decreased in Pak4 KO mice compared to those in WT mice. Fibrosis, as assessed by Sirius Red staining and fibrogenic gene expression, was significantly reduced in Pak4 KO mice. In summary, inhibiting myeloid PAK4 could be a therapeutic option for preventing MASH.