Keloids pose a significant dermatological challenge, marked by abnormal fibroblast proliferation and excessive collagen deposition in response to skin injury or trauma. In the present study, we introduce DMC-HA, a derivative of Curcumin, as a promising candidate for keloid treatment. DMC-HA is poised to provide superior therapeutic benefits compared to Curcumin due to its structural modifications. Examining the comparative effects of DMC-HA and Curcumin on keloid fibroblasts can offer insights into their potential as therapeutic agents and the underlying mechanisms in keloid pathogenesis. In our study, CCK-8 experiments revealed that, at equivalent concentrations, DMC-HA demonstrated greater efficacy in inhibiting the proliferation of keloid fibroblasts compared to Curcumin. Flow cytometry analysis indicated that DMC-HA induced fibroblast apoptosis more significantly than Curcumin at the same concentration. Further data demonstrated that DMC-HA notably increased the production of reactive oxygen species (ROS), upregulated the expression levels of Bax, cleaved PARP, and cleaved Caspase-3. Interestingly, the impact of DMC-HA was reversed upon the application of the antioxidant NAC. Additionally, DMC-HA could suppress IL-6-induced increased expression of p-STAT3. Collectively, our findings suggest that DMC-HA is more effective than Curcumin in inhibiting the proliferation of keloid fibroblasts. The underlying mechanism of its action appears to be associated with the augmentation of ROS induction and the concurrent inhibition of STAT3 activation.