Co-crystals are of considerable relevance to the drug development as they offer the ability of optimizing the physicochemical properties of an active pharmaceutical ingredient by incorporation of a second component (a co-former), while retaining the biological function of the parent material. Co-crystals have been emerged as an alternative approach when salt or polymorph formation does not meet the required targets. Furthermore co-crystals also represent a broad patent space because of the availability of a large number of co-formers. The aim of the present study was to synthesize and delineate co-crystals of paracetamol (a frequently used antipyretic and analgesic drug) and naproxen (a nonsteroidal anti inflammatory drug). Both paracetamol and naproxen had dissolution limited absorption and poor compressional behavior owing to low plasticity. A screening process, employing various methods namely dry grinding, liquid assisted grinding, solvent evaporation and anti solvent addition, was carried out with different ratios of paracetamol and caffeine. Implementation of the screen resulted in paracetamol-caffeine co-crystals by liquid assisted grinding and solvent evaporation methods with 1:1 and 2:1 ratios of paracetamol and caffeine respectively. Naproxennicotinamide co-crystal was generated by liquid assisted grinding in 2:1 molar ratio. Cocrystals gave characteristic PXRD patterns and DSC endotherms that were distinctive from the starting materials. Mechanical properties of paracetamol-caffeine and naproxennicotinamide co-crystals were analyzed by in-die Heckel model and tabletability curves respectively. Mean yield pressure, an inverse measure of plasticity, obtained from the Heckel plots decreased significantly for paracetamol-caffeine co-crystals than pure paracetamol. Over the entire range of compaction pressure used, tensile strength of naproxen was poor and lamination and sticking occurred in some tablets. Tensile strength of naproxennicotinamide co-crystal gradually increased with pressure achieving a desirable value of more than 2 MPa which was ~ 1.80 times that of naproxen at 5000 psi. Moreover, cocrystal pellets did not show any signs of cracking. Intrinsic dissolution rates of co-crystals of both drugs showed more than 2 fold faster dissolution compared to that of the respective pure drugs. Co-crystals were successfully formulated into tablets by direct compression which was not possible to employ for pure paracetamol and naproxen without extensive chipping. In-vitro dissolution studies of paracetamol-caffeine and naproxen-nicotinamide co-crystals based formulations also showed enhanced dissolution profiles in comparison to reference formulations. In a single dose oral exposure study conducted in sheep model both cocrystals revealed a significant increase (p < 0.05) in peak plasma concentration and area under the curve. For selected paracetamol-caffeine and naproxen-nicotinamide cocrystals, peak plasma concentrations were 2.45 and 1.61 times higher corresponding to 2.47 and 1.63 times higher area under the curve as compared to pure paracetamol and naproxen. Relative bioavailability was also found to be ~ 2 and 1.6 times enhanced for PCM and NAP co-crystals, respectively. In conclusion, liquid assisted grinding was found to be a robust and easy method and caffeine and nicotinamide as suitable co-formers for the synthesis of co-crystals of paracetamol and naproxen, respectively. Co-crystals illustrated improved physicochemical and mechanical properties. An enhancement in formulation performance and in-vivo oral bioavailability was also shown by co-crystals.