Co-crystallization brings new opportunities for improving the solubility and dissolution rate of drugs with the chance of finely tuning some relevant chemical–physical properties of mixtures containing bioactive compounds. As co-crystallization process involves several molecular species, which are generally solid at room conditions, its control requires accurate knowledge and monitoring of the different phase that might appear during the formulation stage. In the present study the suitability of X-ray powder diffraction (XRPD) and Fourier-transformed infrared (FTIR) spectroscopy in quantifying mixtures of carbamazepine polymorphs (forms I and III), saccharin, and carbamazepine–saccharin cocrystals (form I) is assessed. Quaternary crystalline mixtures typically produced in the process of co-crystal production were analyzed by multivariate methods. Principal component analysis (PCA) was used for the identification of the crystal phases, while unsupervised simultaneous fitting of the spectra from pure phases, or supervised partial least squares (PLS) methods were used for their quantitative determination. The performance of data analysis was enhanced by applying peculiar pre-processing methods, such as SNIP filtering in case of FTIR and PCA filtering in case of XRPD. It was found that, for XRPD data, the automatic multi-fitting procedures and PLS models developed in this study are able to quantify single phases in mixtures to an accuracy level comparable to that obtained by the widely used Rietveld method, which, however, requires knowledge of the crystal structures. For FTIR data the results here obtained prove that this technique can be used as a fast method for polymorph characterization.