The retinal pigment epithelium (RPE) is continuously exposed to oxidative stress, a major contributor to RPE degeneration in age-related macular degeneration. However, the mechanisms determining RPE cell fate under oxidative stress remain unclear. Here, we uncovered a role of the G protein-coupled estrogen receptor (GPER) in RPE cell survival and examined whether GPER activation uniformly promotes cytoprotection. In human ARPE-19 cells, sodium iodate (NaIO3) reduced GPER protein without altering GPER1 mRNA. Preventing proteasomal degradation restored GPER and PKA phosphorylation, whereas GPER depletion impaired PKA signaling and increased vulnerability to NaIO3. Unexpectedly, two GPER agonists produced different outcomes. G1 was intrinsically cytotoxic and failed to protect against oxidative injury, whereas BJ-2136 preserved GPER-associated cAMP–PKA signaling and improved cell survival. Genetic depletion or pharmacological blockade of GPER and PKA inhibition diminished BJ-2136-mediated protection, whereas 8-Br-cAMP enhanced it. Moreover, suppressing reactive oxygen species alone was insufficient to reproduce cytoprotection. These findings reveal GPER as a regulator of RPE cell survival under oxidative stress and demonstrate that GPER activation does not inherently lead to cytoprotection. Rather, the outcome is determined by ligand-dependent GPER signaling, highlighting selective engagement of the GPER–cAMP–PKA axis as a potential strategy for preserving RPE cell viability.