Objectives: Long non-coding RNAs (lncRNAs) serve pivotal roles in heart disease, while the role of lncRNA hypoxia-inducible factor 1α-antisense RNA 1 (HIF1A-AS1) is rarely mentioned. Therefore, the objective of this study was to investigate the mechanism of lncRNA HIF1A-AS1 regulating suppressor of cytokine signaling 2 (SOCS2) expression by adsorption of microRNA-204 (miR-204) on ventricular remodeling after myocardial ischemia-reperfusion (I/R) injury in mice. Methods: The mouse model of I/R was established by left coronary artery occlusion. The expression of HIF1A-AS1, miR-204 and SOCS2 was determined. The mice were injected with HIF1A-AS1-siRNA, miR-204 mimics or their controls to investigate their effects on cardiac function and ventricular remodeling of mice after I/R injury. The binding relationship between HIF1A-AS1 and miR-204 as well as between miR-204 and SOCS2 were verified. Results: HIF1A-AS1 and SOCS2 were upregulated and miR-204 was downregulated in myocardial tissues in mice after I/R injury. LVEDD, LVEDS, LVEDP, LVMI and RVMI expression reduced while LVEF, LVFS, +dp/dt max and - dp/dt max increased through knockdown HIF1A-AS1 and upregulated miR-204. The expression of BNP, cTnI, LDH, CK, TNF-α, IL-1β, IL-6 and β-MHC reduced, and the expression of α-MHC increased when HIF1A-AS1 was poorly expressed and miR-204 was highly expressed. Silencing HIF1A-AS1 and upregulating miR-204 inhibited apoptosis of cells. LncRNA HIF1A-AS1 could act as ceRNA to adsorb miR-204 to suppress miR-204 expression and elevate SOCS2 expression. Conclusion: Our study provides evidence that downregulation of HIF1A-AS1 and upregulation of miR-204 could alleviate ventricular remodeling and improve cardiac function in mice after myocardial I/R injury via regulating SOCS2.