Hepatic stellate cells (HSCs) are known to play a central role in liver fibrosis (LF), and considered to be a target for LF therapy. We have previously reported that caffeine (CAF) suppresses HSC activation via inhibition of adenosine receptors, while also observing that prostaglandin E₂ (PGE₂) facilitates the inhibitory effect of CAF on HSC activation. However, the mechanism remains to be elucidated. In the present study, we aimed to elucidate the molecular mechanism of the inhibitory effect of PGE₂ and CAF co-treatment. Despite sharing a common pathway for cAMP, intracellular cAMP levels showed no direct correlation with the inhibitory effect of PGE₂ and CAF co-treatment on HSC activation. RNA-seq analysis identified the transcription factor NRF2 as a candidate gene involved in the inhibitory effect of PGE₂ and CAF co-treatment on HSC activation. Reporter assays and immunostaining exhibited that the combination of PGE₂ and CAF resulted in a significant augmentation of NRF2 transcription activity and enhanced nuclear translocation of NRF2. These results suggest that PGE₂ facilitates the inhibitory effect of CAF on HSC activation by amplifying the transcriptional activity of NRF2.