The construction of sluices creates a strong disturbance in water environmental factors within a river. The change in water pollutant concentrations of sluice-controlled river reaches (SCRRs) is more complex than that of natural river segments. To determine the key factors affecting water pollutant concentration changes in SCRRs, river reaches near the Huaidian Sluice in the Shaying River of China were selected as a case study, and water quality monitoring experiments based on different regulating modes were implemented in 2009 and 2010. To identify the key factors affecting the change rates for the chemical oxygen demand of permanganate (CODMn) and ammonia nitrogen (NH3-N) concentrations in the SCRRs of the Huaidian Sluice, partial correlation analysis, principal component analysis and principal factor analysis were used. The results indicate four factors, i.e., the inflow quantity from upper reaches, opening size of sluice gates, water pollutant concentration from upper reaches, and turbidity before the sluice, which are the common key factors for the CODMn and NH3-N concentration change rates. Moreover, the dissolved oxygen before a sluice is a key factor for the permanganate concentration from CODMn change rate, and the water depth before a sluice is a key factor for the NH3-N concentration change rate. Multiple linear regressions between the water pollutant concentration change rate and key factors were established via multiple linear regression analyses, and the quantitative relationship between the CODMn and NH3-N concentration change rates and key affecting factors was analyzed. Finally, the mechanism of action for the key factors affecting the water pollutant concentration changes was analyzed. The results reveal that the inflow quantity from upper reaches, opening size of sluice gates, permanganate concentration from CODMn from upper reaches and dissolved oxygen before the sluice have a negative influence and the turbidity before the sluice has a positive influence on the permanganate concentration from CODMn change rates and that the opening size of sluice gates, NH3-N concentration from upper reaches, and water depth before the sluice have a negative influence and the inflow quantity from upper reaches and turbidity before the sluice have a positive influence on the NH3-N concentration change rates, which provides a scientific grounding for pollution control and sluice operations in SCRRs.