SNX25, a regulator of GPCR signaling‐phox‐homology (PX) domain containing sorting nexin (SNX) member, has been proposed to be involved in the lysosomal degradation of the transforming growth factor β receptor and the development of temporal lobe epilepsy. Targeting to the endosomal membranes by the specific binding of phosphorylated phosphatidylinositols (PIPs) through the PX domain is critical for the function of SNXs. However, the mechanism for SNX25‐PX targeting to the endosomes remains unclear. Here, we demonstrate that the PX domain of zebrafish SNX25 (zSNX25‐PX) is capable of binding to PI3P only in its dimeric form. We also present the crystal structure of zSNX25‐PX. Combined with biochemical experiments, we further identify a potential PI3P‐binding region and propose a novel PI‐binding model based on dimerization in the PX domain of SNXs.