Naringenin (Nar) is a component of fruits and vegetables associated with healthful benefits, such as in osteoporosis, in cancer, and in cardiovascular diseases. These protective effects have been linked with Nar anti-estrogenic as well as estrogenic activities. Previous studies indicate that Nar impaired estrogen receptor (ER) signaling by interfering with ER-mediated activation of ERK and PI3K signaling pathways in the absence of effects at the transcriptional level. The present studies evaluated the hypothesis that these Nar antagonistic effects occur at the level of the plasma membrane. Our results indicate that Nar induces ER de-palmitoylation faster than E2, which results in receptor rapid dissociation from caveolin-1. Furthermore, Nar impedes ER to bind adaptor (MNAR) and signaling (c-Src) proteins involved in the activation of the mitogenic signaling cascades (i.e., ERK and PI3K). On the other hand, Nar induces the ER-dependent, but palmitoylation-independent, activation of p38 kinase which, in turn, is responsible of Nar-mediated anti-proliferative effects in cancer cells. All together these data highlight new ER-dependent mechanisms on the root of anti-proliferative and anti-estrogenic effects of naringenin. Moreover, the different modulation of ER palmitoylation exerted by different ligands represents a pivotal mechanism which drives cancer cell to proliferation or apoptosis.