Aim The previous work showed that momordicin(MD28) can up-regulate the expression of ATP-binding cassette transporter A1 (ABCA1) in THP-1-derived foam cells and reduce the intracellular lipid accumulation, but its mechanism is unclear. This study is to analyze the mechanism of action from the post-transcriptional level. Methods MiRNA chip was used to analyze the microRNA (miRNA) that were down-regulated by 1.5-fold in the miRNA of THP-1-derived foam cells treated with 50 mg/L ox-LDL for 48 h after the intervention of MD28 and compared with the genecards miRNA which regulates the ABCA1 gene expression. Of common miRNA, target gene relationship between this miRNA and ABCA1 was verified by the luciferase reporter gene system. qRT-PCR was used to detect ABCA1 mRNA and miR-23b-3p expression levels, protein was detected by Western blot, oil red O staining was used to detect intracellular lipid accumulation. Results miR-23b-3p was the intersection of miRNA chip and genecards. The target gene validation experiment confirmed that ABCA1 was the target gene of miR-23b-3p. MD28 dose-dependently (0 g/L, 0.4 g/L, 1.2 g/L, 3.6 g/L, 5 g/L) and time-dependently (0 h, 6 h, 12 h, 24 h, 48 h) up-regulated ABCA1 expression, the highest expression level of ABCA1 was at 1.2 g/L for 12 h of MD28. ox-LDL up-regulated the expression of miR-23b-3p and was inhibited by MD28, while MD28 decreased intracellular lipid accumulation, and the inhibitor of miR-23b-3p antagonized the effect of MD28 on ABCA1 expression and intracellular lipid accumulation. Conclusion MD28 can up-regulate the expression of ABCA1 and decrease the intracellular lipid accumulation in THP-1 macrophage-derived foam cells by decreasing the expression of miR-23b-3p.