Many of South Africa’s water quality problems are directly attributable to the negative impacts of anthropogenic land use transformations, including urban and agricultural expansion. To mitigate these impacts, the preservation of an adequate amount of natural vegetation within catchment areas is an important management strategy. However, it is unclear how much natural vegetation cover is required to provide adequate levels of protection, nor at which scale(s) this strategy would be most effective. Accordingly, regression analysis was used to model relationships between water quality (measured using Nemerow’s Pollution Index) and metrics of natural vegetation at multiple scales across a sample of sub-catchments located within South Africa’s Eastern and Western Cape provinces. With conspicuous outliers removed, the models were able to explain between 69 and 82% of variation in the sample. Moreover, a statistically significant, nonlinear, and inverse relationship was found between proportions of natural vegetation cover and pollution levels. This relationship was strongest when measured (1) across the whole catchment and (2) within a 200 m riparian buffer zone. The models further indicated that approximately 80 to 90% natural vegetation cover was necessary at these scales to maintain water quality at ecologically acceptable levels. Additional nonlinear thresholds estimated using breakpoint analysis suggested that if proportions of natural vegetation fall below 45% (across the whole catchment) and 60% (within a 200 m riparian buffer zone) a dramatic increase in pollution levels can be expected.