Optical sensors have emerged as suitable platforms for monitoring health parameters in a personalized fashion and have the potential to revolutionize the way that diabetes is diagnosed and treated. We propose a blood glucose sensor based on a poly(methyl methacrylate) (PMMA) Mach-Zehnder interferometer (MZI) device. The influence of the main structural parameters, including the input/output structure, Y-branch angle, and sensing arm length, on the MZI blood glucose sensor was studied. The experimental results showed that there was a linear relationship between the optical power and glucose concentration in the range of [0, 260] mg/dL. As the glucose concentration increases, the differential optical power decreases approximately linearly, and the sensitivity is 267 mW/(mg/dL). This MZI blood glucose sensor is promising for integration with polymer-based planar waveguides to develop novel photonic devices.