Particulates for pharmaceutical applications require stringent control over their characteristics to realize the optimal therapeutic performance. By generating uniform spray-dried silica particles encapsulating different model drugs via a microfluidic jet spray drying technique, we demonstrated how the effects of formulation and process parameters on the investigated properties could be directly quantified without the complications of wide particle distributions typical of conventional spray drying. The implemented strategies included incorporating lactose to modify the internal microstructures to regulate release, and increasing drying temperature during synthesis to modify the surface features of particles. The physicochemical properties of encapsulated drugs were shown to influence particle morphologies and release profiles, while the pH of initial precursors influenced the particle morphologies with slight effects on the initial release rates. The outcomes would be useful to indentify appropriate formulations and manufacturing parameters in designing spray-dried silica-based microencapsulates with tailor-made controlled release functionalities.