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The tyrosine kinase inhibitor nilotinib has a very low aqueous solubility and a low and variable oral bioavailability. A pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability thereof and of the pharmacokinetics. The aim of this study was to enhance the solubility of nilotinib by developing a spray dried solid dispersion. A broad selection of polymer excipients were tested for solubilizing properties. The spray drying technique was used to produce solid dispersions of nilotinib hydrochloride (NH) in matrices of the best performing polymers. Both the dissolution and physicochemical characteristics of the formulations were studied using a pH-switch dissolution model and conventional microscopic, thermal and spectrometric techniques. Of the tested spray dried solid dispersions, the ones containing the co-block polymer Soluplus® performed best in terms of in vitro dissolution properties. Further testing led to an optimized weight ratio of 1:7 (NH:Soluplus®) that improved the solubility up to 630-fold compared to crystalline NH (1.5 μg/mL) in simulated intestinal fluid. This effect can be attributed to the amorphization of NH and the solubilization of the drug due to micelle formation. A spray dried solid dispersion formulation of NH with Soluplus® in a ratio of 1:7 was developed that showed a significant increase in solubility.