In this work, process analytical technology (PAT) based approaches for controlling the polymorphism and crystal size of a nonsteroidal anti-inflammatory drug (piroxicam) during batch cooling crystallization has been investigated. Previously obtained results regarding the crystallization behavior of the different polymorphs of piroxicam in a small-scale (100 mL) crystallizer have been used to design and to initiate the control approach described in this paper. The results of the present work demonstrated the challenge of reproducing the crystallization process with respect to the product polymorphism at different scales. The solute concentration has been proved to be a critical parameter in determining the polymorphism of piroxicam in the small-scale crystallization experiments; however, the same operation parameters could not yield the same polymorph in the crystallization in 2 L crystallizers. Both direct nucleation control (DNC) and supersaturation control (SSC) have been proven to be effective at controlling the polymorphism of piroxicam in seeded cooling crystallization; furthermore, applying DNC also improved the particulate properties (larger crystal size).