Dual drug encapsulation in biodegradable nanoparticles is always challenging and often requires strenuous optimization of the synthesis–encapsulation processes. This becomes even more difficult when the simultaneous encapsulation of molecules of different polarity is sought. Here we present a modified emulsification–evaporation process to produce polymeric nanoparticles (NPs) made of the biocompatible and biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) and co-encapsulating simultaneously two different drugs, the hydrophobic dexamethasone (DX) and the hydrophilic diclofenac sodium (DS). Three independent processing parameters were systematically modified to promote the incorporation of the different-polarity drugs into PLGA and to control the particle size under 150 nm. The careful selection of the appropriate solvents (ethyl acetate and methanol) was a key requirement for the successful encapsulation of DX and DS. DS and DX release kinetics as well as cytotoxicity assays underlined the therapeutic potential of the dual encapsulation strategy.