Optical biosensor, which perceptively captures the variety of refractive index (RI) of the surrounding environment, has great potential applications in detecting property changes and types of analytes. However, the disequilibrium of light-matter interaction in different polarizations lead to the polarization-dependence and low sensitivity. Here, we propose a polarization-independent and ultrasensitive biosensor by introducing a one-dimensional topological photonic crystal (1D TPhC), where two N-period 1D photonic crystals (PhC1 and PhC2) with different topological invariants are designed for compressing the interaction region of the optical fields, and enhancing the interaction between the light and analyte. Since the strong light-matter interaction caused by the band-inversion is polarization-independent, the biosensor can obtain superior sensing performance both for TE and TM polarization modes. The sensitivity and Figure of Merit (FOM) of the designed biosensor are 1.5677×106 RIU-1 (1.3497 × 106 RIU-1) and 7.8387×1010 RIU-1deg-1 (4.4990×1010 RIU-1deg-1) for TM (TE) polarization mode, which performs two orders of magnitude enhancement compared with the reported biosensors. With the protection of the topological edge state, this biosensor has high tolerance to the thickness deviations and refractive index (RI) variations of the component materials, which can reduce the requirements on fabrication and working environment. It is anticipated that the proposed biosensor possesses excellent sensing performances, may have great potentials in environmental monitoring, medical detection, etc.