For efficient heating and cooling applications, minimum wall shear stress and maximum heat transfer rate are desired. The current study optimized the local skin friction coefficient and Nusselt number in Al2O3-Cu/water hybrid nanofluid flow over a permeable shrinking rotating disk. First, the governing equations and boundary conditions are solved numerically using the bvp4c solver in MATLAB. Von Kármán’s transformations are used to reduce the partial differential equations into solvable non-linear ordinary differential equations. The augmentation of the mass transfer parameter is found to reduce the local skin friction coefficient and Nusselt number. Higher values of these physical quantities of interest are observed in the injection case than in the suction case. Meanwhile, the increase in the magnitude of the shrinking parameter improved and reduced the local skin friction coefficient and Nusselt number, respectively. Then, response surface methodology (RSM) is conducted to understand the interactive impacts of the controlling parameters in optimizing the physical quantities of interest. With a desirability of 66%, the local skin friction coefficient and Nusselt number are optimized at 1.528780016 and 0.888353037 when the shrinking parameter (λ) and mass transfer parameter (S) are −0.8 and −0.6, respectively.