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Changes in LULC and landscape factors impact water quality at spatial and temporal scales. In this study, we investigated the current status in water quality for sub-watersheds of the southern portion of the Nyong River basin of Cameroon from 1994 to 2014 using the WHO guideline. The trends in the water quality parameters were explored using Mann-Kendall test, and their relationship with changes in LULC and landscape factors were analysed using multiple linear regression and Pearson correlation. The current status in water quality did not exceed the WHO guideline limits for drinking water despite a 16% decrease in forest cover and 10% increase in agricultural areas during the period of record. The concentration and changes in water quality trends varied significantly among the sub-watersheds. The concentration of Ca 2+ , Mg 2+ , Na + , SiO 2, K + , DOC, SPM and WT showed significantly increasing trends in the Nsimi small sub-watershed, while only Ca 2+ , Mg 2+ , Na + and NO 3 - showed significantly increasing trends in the large sub-watersheds of Mbalmayo and Olama. A combination of one to five LULC and landscape factors, including changes in urban cover, young secondary forest, slope, elevation and population explained 10 to 70% of the changes in water quality trends at watershed scale. Although the interaction of LULC and landscape factors seems to have low impact on the water quality so far, maintaining greater than 70% forest cover and appropriate fallow farming system is invaluable to protecting water quality in the Nyong River basin in the Congo basin and in other forest-rich regions.