Although flavonoids exhibit a variety of beneficial biological activities, the exact molecular mechanism of the cellular effects is still not fully explained. In this study, we investigated the molecular mechanism of cytoprotective effect of eriodictyol in UV-irradiated keratinocytes. We found that treatment with eriodictyol effectively suppressed the UV-induced cell death of the keratinocytes, concomitant with the inhibition of pro-caspase-3 or pro-caspase-9 cleavage and the suppression of cytochrome C release. The phosphorylation of p38 MAPK was suppressed during UV-induced apoptosis of the keratinocytes and eriodictyol could reverse the down-regulation of p38 MAPK upon UV irradiation. Inhibition of p38 MAPK activity by SB202190, or over-expression of dominant-negative mutant form of p38 MAPK resulted in suppression of cytoprotective effect of the flavonoid. PP2A appeared to participate in the regulation of both p38 MAPK and Akt activities by directly associating with the kinases. UV treatment stimulated not only the phosphatase activity, but also its association with p38 MAPK or Akt. Interestingly, eriodictyol reversed the increase in PP2A activity and the association between the proteins. Taken together, these findings suggest that eriodictyol may lead to protection of keratinocytes from UV-induced cytotoxicity by modulating both the p38 MAPK and Akt signaling pathways in a phosphatase-dependent manner.