Cardiovascular disease, particularly coronary heart disease (CHD), is one of the diseases with the highest fatality. The close correlation between long non-coding RNAs (lncRNAs) and the occurrence and development of myocardial injury has been highlighted recently. This article mainly focused on the regulation of THRIL on myocardial injury caused by CHD in mice. After establishment of a mouse model with CHD, a lncRNA microarray analysis was performed on mouse myocardial tissues to detect differentially expressed lncRNAs, followed by RT-qPCR validation. CHD was induced in mice by high-fat diet feeding and THRIL was silenced using si-THRIL. The results showed that treating CHD mice with si-THRIL attenuated myocardial damage by restoring LVEF, LVFS, and HDL-C levels, while lowering HMI, LVMI, TC, TG, LDL-C, CK-MB, and cTnI levels. Meanwhile, mechanistical studies using bioinformatics prediction, dual-luciferase and subcellular fractionation assays revealed that THRIL bound to microRNA (miR)-424, inhibited miR-424 interaction with TXNIP and promoted TXNIP expression in the myocardial tissues. The cardioprotective effects of si-THRIL on mice were attenuated when miR-424 was downregulated. Moreover, TXNIP exerted its effects on myocardial injury by mediating the p53 pathway. Taken together, this study demonstrated that THRIL inhibition alleviates myocardial injury in CHD possibly through the miR-424/TXNIP/p53 axis.