Mode splitting (MS) in whispering gallery microresonators provides excellent noise suppression in sensing signal compared to mode shifting. Here, we theoretically studied the ability of hollow bottle microresonators for detection of a single nanoparticle in air and water medium by MS phenomenon. To find out the optimum condition of sensor for nanoparticle (NP) detection, the effects of bottle geometry parameters, mode orders, and mode polarization state was investigated. The first radial transverse electric mode demonstrated the best sensitivity when the resonator radius and wall thickness were 10 and 0.3 μm, respectively. However, transverse magnetic modes manifested slightly better detection limit. In the air core hollow microbottle resonator (HMBR), the best detection limit of 3.1 nm radius for polystyrene NPs was achieved at an optimum condition of 30-μm resonator radius and 0.8-μm wall thickness. While MS could not be resolved in deionized water filled HMBRs for all of the investigated conditions at 1550 nm, changing the wavelength to 780 nm provided a detection limit of 15.1 nm in water. Furthermore, it is found that the sensitivity of HMBR is increased by at least two times in comparison with a microtoroid sensor. HMBRs are optofluidic platforms, so employing them could drastically enhance the applicability of microresonator-based systems for label-free NP detection.