The present study aims to design, formulate and evaluate Flurbiprofen (FLB) and Diclofenac Sodium (DCL-Na) once-daily controlled release 100 mg tablets, using various grades of Ethocel® ethylcellulose ether derivative polymer both in-vitro and iv-vivo. FLB and DCL-Na are widely used non-steroidal anti-inflammatory drugs, usually recommended in steroid therapy, and for symptomatic relief of dysmenorrhoea. Optimization of drug substances throughout the determination of some physical and chemical properties is authoritatively ordered in the development of a stable, effective, safe, and reproducible dosage form. The bioavailability of these drugs in gastrointestinal tract is dissolution rate limited. Therefore, during our preformulation work, our efforts encompassed the detailed study of parameters such as particle size, particle size distribution, pH solubility profiles and dissolution behavior of FLB and DCL-Na powders. Differential scanning calorimetery (DSC), Fourier transform infra-red absorption spectroscopy (FTIR), Scanning electron microscopy (SEM), and X-ray diffractomertery (XRD) were exploited as the characterization and evaluation techniques. Solid dispersions of each of FLB and DCL-Na drugs were prepared by solvent evaporation technique. Drug powders, physical mixtures and solid dispersions of each of the drugs were evaluated by different physical methods, including bulk density, tapped density, hausner’s ratio, angle of repose and compressibility index. Different bio-polymeric approaches have been used to the drug release rate and to maintain a steady state plasma concentration throughout the treatment time. Ethylcellulose ether derivative polymers were used to design and formulate oral controlled release hydrophobic matrix tablets prepared by direct compression technique, using a single punch machine. Tablets were subjected to various physical and quality control tests, including thickness, diameter, weight variation, hardness, friability and content uniformity. Tablets were subjected to dissolution test for in-vitro release studies. Later, different kinetic parameters were applied to investigate the drug release mechanism from the polymer based matrix tablets. Diffusion controlled pH independent release with desired zero order kinetics for both the FLB and DCL-Na drugs was an important achievement planned into once-daily controlled released matrix tablets. The controlled released matrix tablets, each of FLB and DCL-Na, containing 30% Ethocel® Standard 7 FP Premium were selected as optimized tablets for further pharmacokinetic studies. Stability of the selected tablets of both FLB and DCL-Na drugs was observed during the short term accelerated stability studies. After selecting optimized test tablets of both FLB and DCL-Na drugs, in-vivo studies were conducted using albino rabbits, using HPLC-based simple, rapid and validated methods. The test ad market formulation were given to the rabbits already fasted for 24 hours. Blood samples were collected from marginal ear vein at predetermined time intervals for 42 hours, and were analyzed by HPLC developed method. In order to investigate the release mechanism in-vivo, various pharmacokinetic parameters, including Cmax, Tmax, AUC0-24, AUC0-inf, MRT, t1/2 and Cltotal for test and reference tablets, were obtained using kinetica software. The best mode of particle size distribution (80-100 μm) of both FLB and DCL-Na was best dissolved in the pH 7.4 phosphate buffer solution and gave maximum absorbance at 247 and 276 nm, respectively. Physical evaluation of the starting materials, including bulk density ranged from 0.250±0.09 to 0.388±0.02, tapped density from 0.250±0.09 to 0.398±0.07, hausner’s ratio from 1.01±0.01 to 1.34±0.08, angle of repose from 11.53 ̊±0.09 to 29.88±0.01, and percent compressibility ranged from 11.21±0.02 to 28.55±0.01%, which were found to be in the best acceptable range, reported in literature. These results showed Ethocel® standard 7 FP premium alone sequentially extended the release of drugs up to 24 hours. Ethocel® helped in maintaining the drugs knotted in its viscous gel layer. The drug release rate could be altered by polymer concentration and particle size. The inclusion of HPMC likely caused slow hydration leading to erosion and drug release by diffusion. While, CMC and Starch-based formulation showed the burst release and completely disintegrated within two hours. Simple and rapid HPLC methods were developed both for FLB and DCL-Na drugs with short retention time of 3.2 and 5.9 minutes, respectively. Optimum levels of both the FLB and DCL-Na Serum concentrations (Cmax) were observed forecasting minimum chances of adverse effects. Significantly prolonged tmax of the test tablets of both FLB and DCL-Na indicated smooth and extended absorption phase of the drugs under study. A good co-relation between the in-vitro drug release and in-vivo drug absorption of the drugs was observed. It was also observed that the area under curves (AUCs) of test tablets and reference tablets were not significantly different (p<0.05) from each other in case of both FLB and DCL-Na drugs. It was concluded that (Ethocel®) ethycellulose ether derivative polymer could be used to prepare once-daily controlled release matrix tablets of FLB and DCL-Na non-steroidal anti- inflammatory drugs.