Coaxial electrospray is an advantageous technique for the fabrication of multidrug-releasing nanocarriers because it enables precise control over particle size and size distribution, limits initial burst release, and has mild preparation conditions. In this work, a coaxial electrospray synthesis method is described achieving nearly 100% layered co-encapsulation of dapagliflozin and indapamide, two drugs treating type 2 diabetes and hypertension, into biodegradable poly (d,l-lactide-co-glicolide) (PLGA) nanoparticles. Scanning electron microscopy showed smooth and elliptic morphology of 708.5–727.7 nm in diameter. Transmission electron microscopy revealed nanoparticles with a trilayer configuration where the inner layer and the middle layer are PLGA with either one of the drugs and the outer layer is PLGA only. Fourier transform infrared spectroscopy confirmed the presence of PLGA, dapagliflozin, and indapamide in all the evaluated formulations. The in vitro release of the two drugs from PLGA carriers in phosphate-buffered saline simulating gastric and intestinal conditions was investigated over seven days. The results demonstrated the sustained and prolonged discharge of dapagliflozin and indapamide from trilayer structures in comparison with that of monolayer NPs. In optimal trilayer structures, 90% dapagliflozin and indapamide were released after 120 and 144 h, respectively, which was 5–6 times slower than monolayer particles. This study indicates that multiple drugs employed for treating type 2 diabetes and hypertension, two pathologies often associated together, can effectively be co-encapsulated in a protective shell of PLGA for therapeutically-advantageous controlled release.