Unidimensional photonic crystal-based biosensors have gained much attention in the area of blood glucose measurement. In this paper, we propose two novel designs based on two-dimensional (2D) Van der Waals materials. The first 1D photonic crystal design consists of multilayers of 2D gallium sulfide and 2D muscovite mica [GaS/Mica]ND[GaS/Mica]N, and the second design consists of multilayers of 2D gallium sulfide [GaS/G]ND[GaS/G]N. We conducted a numerical analysis using the transfer matrix method to investigate the properties of photonic crystals, both with and without defect layers, in order to assess their suitability for biosensing applications. The biosensors’ performances were investigated as a function of glucose concentration, revealing a high sensitivity of 832 nm/RIU, a notable figure-of-merit of 1.46 × 105RIU−1, a Q-factor exceeding 105, and a minimum limit of detection of 3.4 × 10−7RIU. Finally, we modified the [GaS/G]ND[GaS/G]Nstructure in order to enhance the sensitivity nearly 5-fold. The proposed biosensors offer the advantage of being label-free, making them promising platforms for the sensitive and reliable detection of blood glucose levels.