Despite being a common method of manufacturing thermoplastic polyurethane (TPU), the reactive extrusion of these materials is still not well understood. The extruder presents a “black box,” where the feed streams and processing conditions are known, and where the extrudate can be characterized, but the conversion profile along the barrel, and how that changes upon altering the processing conditions, has yet to be characterized. In order to gain insight into the inside the extruder, a model TPU based on an aliphatic isocyanate and polyether backbone was synthesized under various screw speeds, throughputs, and temperatures. In addition to standard process characterizations like residence time distribution, an on-line attenuated total reflectance Fourier transform infrared (ATR-IR) probe/ spectrometer set up was used to characterize the chemical composition of the material inside the extruder at several port locations along the length of the extruder barrel. The results illustrate how challenging it can be to predict the processing behavior of a reactive system.