The littoral zone is an ecological transition zone between land ecosystem and lake ecosystem, which has great environmental heterogeneity and high productivity, and is also vulnerable to human activities. The littoral zone of Lake Hongze is seriously exploited and utilized. In order to explore the spatial differentiation characteristics of water quality, an extensive sampling survey was conducted at 52 sites in the littoral zone in August 2020, and the driving factors of water quality spatial differentiation were explored by stepwise linear regression. The results showed that nitrogen and phosphorus, permanganate index (CODMn) and chlorophyll a (Chla) were the main parameters affecting the water quality of the littoral zone of Lake Hongze. The total nitrogen (TN) concentrations ranged from 0.66 to 4.25 mg·L^-1, with an average of 1.88 mg·L-1, belonging to grade V according GB3838. Total phosphorus (TP) concentrations ranged from 0.02 to 0.24 mg·L^-1, with an average of 0.12 mg·L^-1, which belonged to grade V. CODMn concentration was between 5.24 mg·L^-1 and 14.16 mg·L^-1, with an average value of 7.21 mg·L^-1, belonging to grade IV; Chla concentration ranged from 4.55 to 158.31 ug·L^-1, with an average of 49.30 ug·L^-1. The spatial differentiation of water quality in the littoral zone were large, with CODMn, Chla and dissolved organic carbon (DOC) were higher in Chengzi area and Western area, but lower in Southern area and East area. There was no significant difference in TN and TP concentrations among different areas owning to great variation within a region. The spatial differentiation of water quality in the littoral zone of Lake Hongze is mainly affected by the buffer utilization type, aquatic vegetation coverage and wind wave disturbance, with the buffer utilization type is the most critical factor.