Synthesis of a novel drug delivery system based on active pharmaceutical ingredient (API), ammonium ionic liquid (IL) and grafted–Poly(l-lactide) (API-IL-LA) is presented. Sparingly water-soluble mefenamic acid (MEF) was used as a model drug for the investigation of drug loading efficiency and drug release performance. The synthesis of four ammonium ILs: 2-hydroxyethyl triethyl ammonium bromide, N21-Br, 2-hydroxyethyl tributyl ammonium bromide, N41-Br, di(2-hydroxyethyl)dibutyl ammonium bromide, N42-Br and tri(2-hydroxyethyl)butyl ammonium bromide, N43-Br is described. The synthesized bromide salts were used as an initiator for the ring opening polymerization (ROP) of lactide (LA) with triflic acid as a catalyst. The drug delivery systems of Mefenamate-ammonium-based IL-Polylactide (MEF-IL-LA) were synthesized by metathesis reaction of polylactide ammonium ionic liquid (IL-LA) with silver mefenamate. The (API-IL-LA) compounds, obtained at T = 333 K with different LA:IL ratios 20:1, 40:1 and 80:1 were used for the formulation of nanoparticles (NPs) by an emulsion-solvent evaporation technique. The obtained NPs have spherical shapes and controlled sizes of 279.1 ± 3.6 nm to 453.3 ± 4.9 nm with maximum encapsulation efficiency up to 92.0 ± 2.7%. Solid NPs were evaluated for in vitro release in phosphate–buffered saline (pH = 7.4) by using dialysis bags at temperature T = 310 K. All NPs have shown controlled and sustained release up to 120 h and 168 h, dependent on alkyl chain substituent and the number of hydroxyethyl groups in the molecule, respectively. The data acquired from drug release profiles were correlated by the pseudo-second-order kinetics model. It was observed that formation of ionic pairs between API and polymer matrix decreased API release rate.