Water hyacinth (Eichhornia crassipes) degrades and obstructs the integrity of freshwater ecosystems. However, little attention has been paid to monitoring water hyacinth’s spatial extent, its determinants, and its effects on water quality in Lake Victoria, Uganda. The specific objectives of this paper are to (i) assess the spatial extent and distribution of water hyacinth; (ii) examine the determinants of water hyacinth distribution, and (iii) assess its impact on water quality. High-resolution satellite images (2016–2019) were obtained and used to monitor the spatial extent of the water hyacinth, a household survey was conducted to examine the determinants of the water hyacinth’s extent and patterns while water samples were drawn and analysed for physicochemical properties. Results show that the coverage and distribution of water hyacinth varied over space and time. Water hyacinth coverage primarily increased with a decrease in water surface area. The perceived factors that triggered the water hyacinth spread included the morphology of the Bay, effluent discharge, strong winds, speed of water current, water-level changes, ferry navigation, and construction activities at the shore. Water parameters significantly impacted by hyacinth were pH, TP, BOD, COD, DO, turbidity, and transparency. This study recommends the strict development and implementation of integrated weed control measures, catchment management plans, and point and nonpoint pollution source control.