Co-extrusion is a widely used processing technique for combining various polymers with different properties into a tailored multilayer product. Individual melt streams are combined in a die to form the desired shape. Under certain conditions, interfacial flow instabilities are observed; however, fundamental knowledge about their onset and about critical conditions in science and industry is scarce. Since reliable identification of interfacial co-extrusion flow instabilities is essential for successful operation, this work presents in situ measurement approaches using a novel co-extrusion demonstrator die, which is fed by two separate melt streams that form a well-controlled two-layer co-extrusion polymer melt flow. An interchangeable cover allows installation of an optical coherence tomography (OCT) sensor and of an ultrasonic (US) measurement system, where the former requires an optical window and the latter good direct coupling with the cover for assessment of the flow situation. The feasibility of both approaches was proven for a material combination that is typically found in multilayer packaging applications. Based on the measurement signals, various parameters are proposed for distinguishing reliably between stable and unstable flow conditions in both measurement systems. The approaches presented are well suited to monitoring for and systematically investigating co-extrusion flow instabilities and, thus, contribute to improving the fundamental knowledge about instability onset and critical conditions.