Strong perpendicular magnetic anisotropy (PMA) is crucial for high-performance spintronic devices. However, in transition-metal oxides, it is challenging to achieve an excellent PMA property (anisotropy energy, K_U > 10⁶ erg/cm³), limiting their application potential. Here, we report a pathway to achieve obvious PMA in 3d–5d [nLa_0.67Sr_0.33MnO₃,nSrIrO₃]_m ([nLSMO, nSIO]_m) heterostructures via the cooperation of interfacial engineering and crystal orientation. By depositing multilayers with a (110) orientation, significant PMA is observed despite the fact that the bare LSMO and (001)-oriented heterostructures show in-plane magnetic anisotropy. First-principles calculations suggest that in the (110)-oriented heterosystems, SIO exhibits a large and perpendicular single-ion anisotropy attributed to its strong spin–orbit coupling effect, which leads to the PMA through strong orbital hybridization between Mn and Ir ions at the LSMO/SIO interface. By varying thicknesses (n) of LSMO and SIO, the K_U can be optimized to 4 × 10⁶ erg/cm³. Moreover, the conductive behavior can also be drastically altered between insulation and metallicity with the n change, implying the potential for simultaneously obtaining ferromagnetic metals and insulators with sizable PMA in one oxide heterosystem. These findings highlight the importance of interfacial engineering and crystalline orientation in tuning PMA in oxides and provide a feasible route for developing high-performance oxide-based spintronic devices.