β‐Arrestin2 has been identified to act as a corepressor of androgen receptor (AR) signaling by binding to AR and serving as a scaffold to affect the activity and expression of AR in androgen‐dependent prostate cancer cells; however, little is known regarding its role in castration‐resistant prostate cancer (CRPC) progression. Here, our data demonstrated that β‐arrestin2 contributes to the cell viability and proliferation of CRPC via the downregulation of FOXO1 activity and expression. Mechanistically, in addition to its requirement for FOXO1 phosphorylation induced by IGF‐1, β‐arrestin2 could inhibit FOXO1 activity in an Akt‐independent manner and delay FOXO1 dephosphorylation through the inhibition of PP2A phosphatase activity and the attenuation of the interaction between FOXO1 and PP2A. Furthermore, β‐arrestin2 could downregulate FOXO1 expression via ubiquitylation and proteasomal degradation. Together, our results identified a novel role for β‐arrestin2 in the modulation of the CRPC progress through FOXO1. Thus, the characterization of β‐arrestin2 may represent an alternative therapeutic target for CRPC treatment. J. Cell. Physiol. 230: 2371–2381, 2015. © 2015 Wiley Periodicals, Inc.