Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib (IBR), belongs to class II of the Biopharmaceutics Classification System (BCS). CYP3A4 enzyme forces IBR to have a very limited oral bioavailability. This study employed hot-melt extrusion (HME) with carboxylic and carboxamide coformers, guided by computational screening, to prepare and characterize IBR cocrystals (IBR-CC). Several carboxylic acid and carboxyl amide coformers were chosen in accordance with computational evaluations and predictions for the solubility parameter to formulate IBR-CC. According to the computational results, the formulated IBR-CC systems had multiple hydrogen bonds and π-π-stacking interactions. The IBR-CC formulations were further evaluated for powder dissolution studies, flow properties, and in vitro release studies. Furthermore, IBR-CC formulations were correlated with better anticancer action in K562-CCL-243 cancer cells when compared with IBR. From the in vivo pharmacokinetic evaluation studies, it was proven that the IBR oral bioavailability in IBR-Nicotinamide-cocrystal formulation has shown a 4.58-fold improvement, IBR-Fumaric acid-cocrystal formulation has shown a 2.66-fold improvement, and IBR-3-Hydroxy benzoic acid has shown a 1.76-fold enhancement when compared with pure IBR suspension. Biodistribution studies showed greater drug release in the intestine and other lymphoid organs when administered with IBR-Nicotinamide-cocrystal formulation than pure IBR suspension. As a result, the IBR-CC formulations produced utilizing the HME approach serve as an effective method of drug delivery that increases IBR's solubility and oral bioavailability.