The objective of this study was to evaluate the effects of processing methods and heat treatment on matrix formation and subsequent drug release from wax matrix tablets for controlled release. Phenylpropanolamine hydrochloride (PPA) and Compritol® were processed with appropriate diluent(s) using either dry blending (DB), wet granulation (WG), partial melt granulation (PMG), or melt granulation (MG). Then the tablets were heat-treated at 80°C. Particle size distribution and compressibility, along with drug release, tablet micro-morphology, wettability, porosity, and tortuosity were investigated. The drug release was different for the four processing methods even though the tablet formulation was identical. Heat treatment further retarded drug release and its effect was related to the previous manufacturing processes. Scanning Electron Microscopy (SEM) showed that heat treatment redistributed the wax and formed a film-like structure covering drug and excipients. The contact angle of tablets made from DB, WG, and PMG methods increased after heat treatment, while that of tablets made from DB, WG, and PMG methods increased after heat treatment, while that of tablets made from MG remained constant. Tablet tortuosity calculated from drug release rate constants increased dramatically after heat treatment. Drug release from the wax tablets with or without heat treatment was best described by the Higuchi equation. Different processing methods produced different matrix structures that resulted in different drug release rates. Heat treatment retarded drug release mainly by increasing tortuosity of the matrix. Contact angle measurement and SEM analysis indicated that heat treatment caused the wax to melt, redistribute, coat the drug and diluents, and form a network structure.