The sensing performance of N-polar GaN/InAlN MOS-HEMT biosensors for neutral biomolecules was investigated and compared with the Ga-polar MOS-HEMT and N-polar T-gate HEMT by numerical simulation. The results indicate that the N-polar GaN/InAlN MOS-HEMT biosensor has higher sensing sensitivity than the Ga-polar MOS-HEMT and N-polar T-gate HEMT biosensors. Furtherly, to improve the sensing performance of N-polar MOS-HEMT, the influence of cavity dimensions, GaN channel layer thickness, and InAlN back barrier layer thickness on device performance was investigated. It is demonstrated that the sensitivity of the biosensor increases as the cavity height decreases and the cavity length increases. Therefore, the sensing performance of the N-polar MOS-HEMT device will be enhanced by thinning the GaN channel layer thickness or increasing the InAlN back barrier thickness, which can be mainly attributed to the variation of the energy band structure and 2DEG concentration in the HEMT heterostructure. Finally, the highest sensitivity can be obtained for the N-polar MOS-HEMT with 6-nm-thick GaN channel layer, 30-nm-thick InAlN back barrier layer, and two 0.9-μm-long and 5-nm-high cavities. This work provides structural optimal design guidance for the N-polar HEMT biosensor.