<p>Orbital angular momentum has recently been demonstrated as a promising approach to manipulate magnetic order in spintronic devices with high efficiency. While the generation of orbital angular momentum is generally attributed to electron orbital hopping and hybridization, its experimental manifestations have often been discussed in an isotropic manner. In crystalline systems, however, orbital hybridization is inherently constrained by crystal symmetry, suggesting that symmetry can play a decisive role in shaping the anisotropy of orbital angular momentum-related responses. In this work, we report a crystal-symmetry-dependent orbital Rashba-Edelstein effect in a distinct epitaxially grown CuO thin film with four-fold crystal symmetry. A crystal-symmetry-dependent sign change of spin torque efficiency is observed in the CuO/ferromagnetic heterostructures, verified by second harmonic Hall measurement and current-induced perpendicular magnetization switching. The experimental results, together with the first-principles calculation, indicate the existence of a strong four-fold anisotropy of orbital Rashba-Edelstein effect in crystalline CuO, which is a direct manifestation of the crystal symmetry’s impact on the anisotropy of orbital angular momentum-related response. These findings establish crystal symmetry as a key factor governing the anisotropy of orbital angular momentum-related phenomena and provide a symmetry-based framework for orbitronic functionalities in advanced spintronic devices.</p>