Implantable luminescent sensors are being developed for on-demand monitoring of blood glucose levels. For these sensors to be deployed in vivo, a matched external hardware system is needed. In this paper, we designed a compact, low-cost optical system with highly efficient photon delivery and collection using advanced optical modeling software. Compared to interrogation with a fiber bundle, the new system was predicted to improve interrogation efficiency by a factor of 200 for native sensors; an improvement of 37 times was predicted for sensors implanted at a depth of 1 mm in a skin-simulating phantom. A physical prototype was tested using silicone-based skin phantoms developed specifically to mimic the scattering and absorbing properties of human skin. The experimental evaluations revealed that the prototype device performed in agreement with expectations from simulation results, resulting in an overall improvement of over 2000 times. This efficient system enables use of a low-cost commercial spectrometer for recording sensor emission, which was not possible using only fiber optic delivery and collection, and will be used as a tool for in vivo studies with animal models or human subjects.