The expanding cropland profoundly affects stream water quality. However, the relationships between landscape patterns and stream water quality in different cropland composition classes remain unclear. We observed total nitrogen (TN), total phosphorus (TP) concentrations, and landscape patterns changed in 78 sub-watersheds of the Taihu Lake Basin’s Jiangsu segment from 2005 to 2020. The results showed that cropland area was positively correlated with TN and TP concentrations. The 21.10% reduction in cropland area, coupled with a 41.00% increase in building land, has led to an escalation in cropland fragmentation. Meanwhile, TN and TP concentrations declined by 26.67% and 28.57%, respectively. Partial least squares suggested that forest interspersion and juxtaposition metrics and forest area percentage were dominant factors influencing water quality in high- and medium-density cropland zones, respectively. The Cellular Automata–Markov Model shows reasonable distribution of forests. Scenarios with enhanced forest interspersion and juxtaposition metrics (75.28 to 91.12) showed reductions in TP (26.92% to 34.61%) and TN (18.45% to 25.89%) concentrations by 2025 compared to a natural economic development scenario. Landscape configuration optimization could assist managers in improving water quality.