BACKGROUND AND PURPOSE: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti‐inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. EXPERIMENTAL APPROACH: Human THP‐1 cells and HUVECs were used as in vitro models. Western blots and real‐time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by (3)H labelling of cholesterol. LDL receptor knockout (Ldlr (−/−)) mice fed a high‐fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. KEY RESULTS: Using ATP‐binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m‐6, which enhances ABCA1 expression and promotes cholesterol efflux in THP‐1 macrophages. Moreover, 1m‐6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1‐regulating miRNAs through nuclear factor erythroid 2‐related factor 2 (Nrf2)/haem oxygenase‐1 (HO‐1) signalling. Additionally, 1m‐6 significantly inhibits TNF‐α‐induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM‐1) and intercellular adhesion molecule 1 (ICAM‐1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO‐1 signalling in HUVECs. In atherosclerosis‐prone mice, 1m‐6 significantly reduces lipid accumulation and atherosclerotic plaque formation. CONCLUSION AND IMPLICATIONS: Our study demonstrates that 1m‐6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation‐induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc
