In this work, a unique Photonic Crystal Fiber based on the Localized Surface Plasmon Resonance is designed for cancer cell and chemical detection. A novel combination of plasmonic materials namely Aluminum doped Zinc Oxide (AZO) and a Silver (Ag)-TiO2 bilayer is deposited along two horizontal slits to achieve resonance at two separate wavelengths within a particular refractive index. The sensor achieves resonance at different wavelengths along x and y polarizations, broadening analyte detection for a specific RI. Two modes of operation are introduced: mode-1 is optimized to achieve the highest Amplitude Sensitivity (AS), and mode-2 to maximize the Wavelength Sensitivity (WS). The mode-1 is examined for a range of RI from 1.35 to 1.42, while the other is 1.35–1.41. The sensor can showcase an AS of 4641.51 RIU−1 for Ag at RI 1.36, which is the highest value of AS found in literature when Ag is used as plasmonic material, while AZO achieves a high AS of 3204.51 RIU−1 at 1.41 RI. A highest WS of 10,320 and a Double Peak Shift Sensitivity (DPSS) of 8089.5 nm/RIU at 1.41 RI is obtained using the mode-2 configuration with a wavelength resolution of 9.69 × 10−6 RIU and a maximum FOM of 568.22 RIU−1. The sensor is examined to investigate skin, cervical, and blood cancer by analyzing the Basal, HeLa, and Jurkat cells, which yielded superior outcomes when detected using AS among relevant works. In addition, the detection of various industrial chemicals like acetone, hexane, isopropanol, and ethanol is also manifested in this study.