We theoretically study a quantum destructive interference (QDI)-induced photon blockade in a two-qubit driven cavity quantum electrodynamics system with dipole–dipole interaction (DDI). In the absence of dipole–dipole interaction, we show that a QDI-induced photon blockade can be achieved only when the qubit resonance frequency is different from the cavity mode frequency. When DDI is introduced the condition for this photon blockade is strongly dependent upon the pump field frequency, and yet is insensitive to the qubit–cavity coupling strength. Using this tunability feature we show that the conventional energy-level-anharmonicity-induced photon blockade and this DDI-based QDI-induced photon blockade can be combined together, resulting in a hybrid system with substantially improved mean photon number and second-order correlation function. Our proposal provides a nonconventional and experimentally feasible platform for generating single photons.