Background: Previous research demonstrated that emodin inhibits cardiac fibrosis through metastasisasspcoated protein 3 (MTA3), but its limited bioavailability hinders clinical application. Aim: To enhance emodin clinical potential, a new derivative, emodin succinyl ethyl ester, was synthesized by modifying the 3’-OH position. This study assessed its drug-likeness, anti-fibrotic properties, and molecular mechanisms involving MTA3. Methods: Drug-likeness properties of the emodin derivative were evaluated using computational-aided drug design (CADD) approaches. An animal model of transverse aortic constriction (TAC)-induced cardiac fibrosis and Angiotensin II (AngII) stimulated cardiac fibroblasts were used in vivo and ex vivo, respectively, to determine the effects of emodin derivative on cardiac fibrosis and fibroblast transdifferentiation. Bioinformatics analysis of the PROMO database, CADD, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and functional experiments were employed to predict, identify and validate the relationship between MTA3 and its upstream transcription factors. Results: Emodin derivative exhibited superior drug-likeness and anti-fibrotic effects compared to emodin by effectively inhibiting cardiac fibroblast transdifferentiation and restored MTA3 expression. E2F1 was identified and validated as a transcriptional regulator, promoting α-SMA and COL1A2 expression, and directly reducing MTA3 expression in cardiac fibroblasts. The emodin derivative demonstrated stronger binding to E2F1 transcription site than emodin, reducing E2F1 expression and enhancing anti-fibrotic action via MTA3. Conclusion: The emodin derivative shows improved drug-likeness and potent inhibition of cardiac fibrosis by targeting E2F1, disrupting its pro-fibrotic function, restoring MTA3 expression, and halting fibrosis progression. This advances emodin’s potential as a clinical therapy for cardiac fibrosis and provides insights into its anti-fibrotic mechanisms.