Efficient nutrient management is imperative to control nutrient losses from farmland in the Erhai Lake Basin (ELB). To address this, a two-year field experiment (2021–2022) was conducted in the northern part of the ELB. The study aimed to quantify the impact of various fertilization treatments on nitrogen (N) and phosphorus (P) losses. The four fertilizer treatments included: no fertilizer (CK), farmer’s fertilizer-purely organic fertilization (FP), chemical fertilizer (CF), and a combination of organic and inorganic fertilizers (OIC). The OIC treatment significantly decreased N losses throughout the entire flue-cured tobacco season compared to the FP treatment, reducing TN runoff losses by 2.68 kg ha− 1 and TP runoff losses by 0.10 kg ha− 1. For leaching losses, the OIC treatment demonstrated a reduction of 21.3% in total N (TN) losses and 17.3% in total P (TP) losses compared to the purely organic fertilization treatments. Regarding yield and economic, the two-year average yield of the OIC treatment was 2573.93 kg ha− 1, a 3.8% increase compared to the FP treatment, accompanied by a significant rise in economic value. Correlation analysis revealed that soil available N and soil water content were key factors significantly influencing TN and TP runoff losses. These findings offer a theoretical foundation for the control of nutrient losses in farmland in the ELB.