Novel non-toxic cellulose acetate butyrate (CAB) bilayer coated microspheres of gelatin (GE) prepared without using a cross-linker were used for investigating the controlled release of ciprofloxacin (CFX). The microspheres were characterized by Fourier transform infrared spectroscopy to understand CAB coating and its chemical inertness towards CFX. Differential scanning calorimetry was used to investigate the molecular level drug dispersion into the polymer matrix, while scanning electron microscopy was used to investigate the surface morphology of the formulated microspheres. Mean particle sizes ranged between 240 and 847 μm, while equilibrium water uptake performed in double distilled water ranged between 492 and 3152%. The drug loaded formulations exhibited high encapsulation efficiency up to 91%. The in vitro release studies performed in acidic and alkaline media indicated influence of GE and CFX content as well as amount of CAB coating on the release characteristics of CFX that was extended up to 20 h. Analysis of in vitro results using empirical equations suggested a non-Fickian release mechanism.