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Objectives: To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD). Background: The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited.Methods: In vivo , we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice assessment of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). We used siRNA to knock down Herpud1 in cultured Primary AVICs were isolated from mice to further validate our findings. Results: Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in high methionine diet–fed low-density lipoprotein receptor-/- (LDLR-/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis. Conclusions: These findings identify a previously unknown mechanism of Herpud1 upregulation in CAVD progression, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression.