This study presents the design and analysis of a surface plasmon resonance biosensor based on a photonic crystal fiber. Two honeycomb configurations-a point‑top hexagonal structure and a flat‑top structure rotated by 60°-were examined to evaluate the influence of air‑hole arrangement on the plasmonic response. Simulations were performed in COMSOL 6.3 using a PCF‑based architecture to achieve effective coupling between the guided mode and the surface plasmon polariton. Results indicated that the point‑top configuration provides better phase matching with the SPP mode and yields a higher confinement loss of 37.83 dB/cm compared to 35.71 dB/cm. Wavelength‑based sensitivity analysis within the refractive‑index range of 1.35-1.40 revealed high sensitivities for both designs, with the point‑top configuration achieving a superior value of 936.26 nm/RIU versus 929.75 nm/RIU in the flat‑top design. Both structures exhibited increased loss and a redshift in resonance wavelength as the analyte refractive index increased. In distinguishing healthy and cancerous skin and blood cells, the point‑top sensor produced larger resonance wavelength shifts (65 and 80 nm) than the flat‑top sensor (60 and 70 nm), indicating higher accuracy. Binomial regression (R² > 0.99) further confirmed the superior fitting quality of the point‑top configuration. Overall, optimizing air‑hole geometry and plasmonic characteristics plays a crucial role in enhancing SPR‑PCF biosensor performance and supports the development of next‑generation high‑efficiency biosensing devices.