Acute myocardial infarction (AMI) is a severe cardiovascular condition. Recently, it has been discovered that dioscin plays pivotal roles in the domains of anti-inflammatory, antiviral, and anti-tumor activities. However, Nevertheless, the precise impact and mechanism by which dioscin protects against cardiomyocyte pyroptosis in AMI remains unclear. This study aimed to determine the significance and investigate the mechanisms by which dioscin affects cardiomyocyte pyroptosis in cases of acute myocardial infarction. In this study, rats were divided into four distinct groups: sham, AMI, AMI + Negative Control (NC), and AMI + FGD5 Antisense RNA 1 (FGD5-AS1). Subsequently, quantitative real-time polymerase chain reaction (qPCR) assay, quantification of infarct size, and enzyme linked immunosorbent assay (ELISA) assay were used to confirm the expression of FGD5-AS1 after AMI surgeries. The results indicated that, expression of FGD5-AS1 was significantly decreased. Furthermore, it was determined that FGD5-AS1 can alleviate myocardial damage induced by AMI. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and western blot assay results indicated that FGD5-AS1 promoted cell proliferation and decreased the inflammatory response and pyroptosis of cardiomyocytes induced by hypoxia/re-oxygenation (H/R). In addition, a combination of bioinformatics approaches, dual-luciferase reporter assay, and RNA pull down assay were used to predict and confirm the interaction between FGD5-AS1, microRNA-424 (miR-424), and Homeobox A3 (HOXA3). It was observed that FGD5-AS1 facilitates cell proliferation and alleviate H/R-induced inflammatory response and cardiomyocyte pyroptosis by regulating HOXA3 expression. Finally, the confirmation of dioscin’s ability to mitigate myocardial damage and cardiomyocyte pyroptosis resulting from acute myocardial infarction (AMI) and regulating the expression of FGD5-AS1/miR-424/HOXA3 axis was established. Together, this research demonstrates that dioscin effectively reduces cardiomyocyte pyroptosis in rats with acute myocardial infarction (AMI) by modulating long non-coding RNA (LncRNA) FGD5-AS1/miR-424/HOXA3 axis.