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Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. PCSK7-SNPs gain-of-function and loss-of-function variants were associated with higher and lower levels of plasma apoB and TGs, respectively. Herein, we biochemically defined the in vivo role of PCSK7 in lipid metabolism using full-body Pcsk7-/- mice and hepatic cell lines. Non-enzymatically membrane-bound PCSK7 binds apoB100 in the endoplasmic reticulum and enhances its secretion. Mechanistically, the loss of PCSK7/Pcsk7 leads to apoB degradation, triggering an unfolded protein response, autophagy, and β-oxidation, eventually reducing hepatic lipid accumulation. We investigated whether Pcsk7-/- mice could better recover from a NAFLD-inducing 12-weeks high fat/fructose/cholesterol diet when followed by a 4-weeks regular diet. Livers of Pcsk7-/- mice more effectively and safely recovered than those of wild-type mice. These findings were validated following subcutaneous administration of hepatocyte-targeted N-acetylgalactosamine (GalNac)-antisense-oligonucleotides (ASOs) against Pcsk7, strongly supporting the therapeutic intervention of hepatocyte PCSK7 mRNA silencing for NAFLD treatment.