The work aims to study the laws of impact that molybdenum disulfide (MoS2) particle size has on the self-lubricating and wear resistance of thermoplastic polyurethane (TPU) polymer materials, and to improve the tribological properties of TPU. For these purposes, a new TPU matrix composite composed of TPU and four different sizes (50 nm, 500 nm, 5 μm, 50 μm) of MoS2 particles was fabricated by physical blending. The RTEC wear test apparatus was used to test the tribological properties of modified TPU composites under water-lubricated conditions in low friction velocity and heavy load. The mechanism through which the effect of different particle sizes of molybdenum disulfide on friction and wear mechanism of modified TPU composite was revealed by analyzing the typical mechanical properties, coefficient of friction (COF), wear morphology, wear rate and element composition and distribution on the wear interface of the friction pairs. The results showed that the MoS2 tribo-film formed during the friction process effectively reduced the COF and TPU deformations on wear surface although the mechanical properties of the TPU were weakened by MoS2. The tensile strength of the modified TPU composites increased firstly and then decreased with the declining of MoS2 particle size and TPU modified by 500 nm MoS2 exhibited the highest values of 33.8 MPa. The similar trend could be seen in the elongation at break of modified TPU composites and the elongation at break of TPU modified by 500 nm MoS2 was the highest, approximately 334.55%. The average COF and volume stroke wear rate of the modified TPU composites decreased earlier and later increased with the reduction of MoS2 particle size and TPU modified by 500 nm MoS2 presented the lowest average COF and wear rate of 0.093 and 0.12×10-3mm3/ (N m) respectively, which were reduced by 58.1% and 97.8% respectively in 40 N compared with pure TPU. Furthermore, the results of longtime wear test under the same conditions showed that the COF curve of TPU modified by 500 nm MoS2 always maintained lower and more stable state compared with TPU modified by 5 μm MoS2, and the totals mass fraction of sulfur and molybdenum element in the wear area of Al2O3 ball sliding against with TPU modified by 500 nm MoS2 was the highest, approximately 34.95 wt.%. These phenomena indicated that the small particle size of MoS2 had more outstanding abilities of transferring to the wear interface and adsorbing on the wear surface of friction pair, which resulted in reducing the COF and extending the duration in low COF period. In summary, appropriate particle size of MoS2 promotes the formation of MoS2 tribo-film at the wear interface and inhibits the reduction of mechanical properties of modified TPU composites, and reduces the COFs and wear volumes. The findings obtained in this study provide a reference for designing and developing the water-lubricated stern tube bearing polymers with low friction and high wear resistance.