Coprocessing via spray drying was applied to improve the compactability of acetaminophen and to select an optimal formulation. Four-component mixtures containing acetaminophen, mannitol, erythritol, and maltodextrin were produced by cospray drying. A D-optimal mixture design was constructed to evaluate the spray dried powder and tablet properties. An increasing mannitol and erythritol content improved powder flowability and density. However, a higher erythritol concentration in the spray dried powder mixture had a negative influence on tablet tensile strength and friability. A higher maltodextrin content increased tablet tensile strength and improved tablet friability, while disintegration time, average particle size, powder flowability, density, and hygroscopicity were negatively influenced.