Calcific aortic valve disease (CAVD) is featured by thickening and calcification of the aortic valve. Osteoblast differentiation is a crucial step in valve calcification. Long non-coding RNAs (LncRNAs) participate in the osteogenic differentiation of mesenchymal cells. However, the character of lncRNA FGD5 antisense RNA 1 (FGD5-AS1) in CAVD is uncertain. After collection of human aortic valve tissue samples, detection of FGD5-AS1, microRNA (miR)-497-5p and Baculovirus inhibitor 5 (BIRC5) was conducted. Valve mesenchymal cells were isolated from CAVD patients and induced to differentiate to osteoblasts, and transfected with FGD5-AS1, miR-497-5p and BIRC5 plasmids. Detection of the alkaline phosphatase activity was after osteogenic induction of human aortic valve interstitial cells (hAVICs); Detection of the degree of calcium nodules and osteoblast differentiation markers (RUNX2 and OPN) was conducted. After establishment of a mouse model of CAVD, detection of the thickness of aortic valve leaflets, and the degree of calcification of the valve leaflets, and evaluation of echocardiographic parameters were implemented. Experimental data manifested in CAVD patients, lncRNAFGD5-AS1 and BIRC5 were reduced, but miR-497-5p was elevated; Enhancing lncRNA FGD5-AS1 or repressing miR-497-5p mitigated CAVD by restraining osteogenic differentiation; LncRNA FGD5-AS1 sponged miR-497-5p to target BIRC5; Repressive BIRC5 turned around the therapeutic action of elevated FGD5-AS1 or depressed miR-497-5p on hAVICs; Enhancive FGD5-AS1 in vivo was available to reduce ApoE-/- mouse CAVD induced via high cholesterol diet. All in all, lncRNAFGD5-AS1 targets BIRC5 via miR-497-5p to alleviate CAVD.