AbstractSuperfluidity, first discovered in liquid ⁴He, is closely related to Bose–Einstein condensation (BEC) phenomenon. However, even at zero temperature, a fraction of the quantum liquid is excited out of the condensate into higher momentum states via interaction-induced fluctuations—the phenomenon of quantum depletion. Quantum depletion of atomic BECs in thermal equilibrium is well understood theoretically but is difficult to measure. This measurement is even more challenging in driven-dissipative exciton–polariton condensates, since their non-equilibrium nature is predicted to suppress quantum depletion. Here, we observe quantum depletion of a high-density exciton–polariton condensate by detecting the spectral branch of elementary excitations populated by this process. Analysis of this excitation branch shows that quantum depletion of exciton–polariton condensates can closely follow or strongly deviate from the equilibrium Bogoliubov theory, depending on the exciton fraction in an exciton polariton. Our results reveal beyond mean-field effects of exciton–polariton interactions and call for a deeper understanding of the relationship between equilibrium and non-equilibrium BECs.