<p>Wheat (<i>Triticum aestivum</i> L.) is a key staple crop globally and is vital for food security in Ethiopia. However, cereal production is constrained by stem rust (<i>Puccinia graminis f. sp. tritici</i>), particularly in hotspot areas. Agronomic practices such as nitrogen (N) fertilization and fungicide influence the disease development and yield. This study was conducted to assess the interactive effects of wheat variety, nitrogen rate, and fungicide application frequency on stem rust and yield in wheat. Three varieties (Ogolcho-susceptible, Kingbird-moderately resistant, and Wane-resistant), three nitrogen rates (100, 150, and 200&#xa0;kg N ha⁻¹), and three fungicide frequencies (unsprayed, one spray, and two sprays of Nativo® SC 300) were evaluated. Variety, nitrogen rate, fungicide frequency, and their interactions significantly (p &lt; 0.01) affected disease severity and yield components. The highest stem rust severity (77%) and AUDPC (1250%-days) were recorded in unsprayed plots with Ogolcho receiving N fertilizer at 200&#xa0;kg N ha⁻¹. Fungicide application reduced rust severity by up to 100% and improved yield by 87–90% relative to unsprayed control. The highest grain yield (3627&#xa0;kg ha⁻¹) was obtained from Wane with 200&#xa0;kg N ha⁻¹ and two fungicide sprays. Overall, integrating resistant varieties with balanced nitrogen application and timely fungicide sprays reduced stem rust and enhanced wheat productivity. However, further validation through multi-location and multi-year trials across different agro-ecological zones is recommended to confirm the consistency of these results.</p>