The “Drying-redissolution” method is promising for the industrial production of high-concentration well-dispersed graphene oxide slurry (GOS). As the potential key step in this method, the spray drying process requires a statistical investigation which guides the large-scale preparation of graphene oxide powder (GOP). This work systematically studies the effects of operating parameters, including nozzle airflow rate (439–895 L·h−1), atomization pressure (0.5–0.7 MPa), and liquid feed rate (3.0–9.0 mL·min−1), by using the response surface methodology integrated Box–Behnken design (RSM–BBD), aiming to produce GOP with high yield and easy re-dispersion. The optimized spray drying condition is predicted to be 439 L·h−1, 0.59 MPa, and 9.0 mL·min−1, at which a powder yield of 70.45% can be achieved. The experimentally obtained GOP has an average particle size of 11.65 μm and the low crumpling degree of the particle morphology results in the good re-dispersibility (97.95%) and excellent adsorption performance (244.1 mg·g−1) of GOP. The GOS prepared by the spray-dried GOP possess low viscosity and high exfoliation efficiency with a single-layer fraction up to 90.8%, exhibiting good prospects for application. This work first applied the RSM–BBD model on the spray drying process of GO, and evidenced the possibility of producing high-quality GO slurry with the “drying-redissolution” method.