The present investigation involves preparation, optimization, and evaluation of the Cilnidipine (CLN) nanosuspension to enhance the dissolution rate and bioavailability. CLN nanosuspension was formulated by precipitation-ultrasonication method. The factors affecting the formulation of CLN nanosuspension were screened by Plackett–Burman design. The screened parameters (concentration of drug, agitation speed, and concentration of Tween 80) were used to optimize the CLN loaded nanosuspension using Box Behnken (BB) design. Optimized formulation was evaluated for particle size (nm), zeta potential (mV), PDI, entrapment efficiency (%), and in-vitro dissolution study. Compatibility studies of the optimized formulation were carried out by Fourier transform-infrared spectroscopy, powdered x-ray diffraction, scanning electron microscopy, and transmission electron microscopy. Further, in-vivo performance of the optimized formulation was investigated and was compared with the marketed product. The optimized formulation demonstrated desirable results for particle size (280.1 ± 3.7 nm), PDI (0.176), zeta potential (−13.9 ± 0.9 mV), percent entrapment efficiency (92.14 ± 0.97%), and in-vitro dissolution at 40 min (100.23 ± 1.63%). The compatibility studies demonstrated no interactions between drug and excipients. Scanning electron microscopy and transmission electron microscopy analysis illustrated the spherical shape of the particle with uniform distribution. Further, In-vivo pharmacokinetic study indicated significant increase (P<0.005) in C_max (23.67 ± 1.50 ng/ml), t_max (0.25 h), and AUC (0–t) (94.26 ± 2.19 ng.h ml⁻¹) when compared to the CLN and marketed formulation. In conclusion, the present investigation of the nanosuspension approach can enhance the solubility and dissolution of the poorly water-soluble drug with improved bioavailability, resulting into better oral absorption than the conventional dosage form and pure drug.