<p>Maize (<i>Zea mays</i> L.) is the most important cereal crop in Ghana but yields still fall short of potential due to poor soil fertility and suboptimal nitrogen (N) management. This study assessed the interactive effects of four maize varieties (<i>Wang dataa, Sanzal-sima, Salin-kawana,</i> and <i>Opeaburo</i>) and four N fertilizer rates (0, 60, 90, and 120&#xa0;kg N ha⁻¹) on growth, yield components, and grain production across two consecutive seasons (2023 and 2024) in the Guinea Savanna agroecological zone of Ghana. A 4 × 4 factorial experiment was conducted using a randomized complete block design with four replications, testing the four maize varieties under the four N rates. Data on growth and yield were collected and analyzed using analysis of variance and polynomial regression. Results showed significant (<i>p</i> &lt; 0.05) main and interaction effects of variety and N rate on most traits measured. Nitrogen application improved plant height, stover biomass, chlorophyll content, and grain yield, with differences among varieties in responsiveness. <i>Wang dataa</i> and <i>Salin-kawana</i> exhibited better yield responses at higher N levels, while <i>Sanzal-sima</i> was less responsive. Grain yield increased up to 4.7 t ha⁻¹ with 120&#xa0;kg N ha⁻¹, representing over 120% yield increase compared to the unfertilized control. Regression analysis showed a positive but non-linear response to higher N, with the quadratic term significant in the second season (R² = 0.78, <i>p</i> &lt; 0.05), indicating diminishing returns beyond moderate N levels. These findings emphasize the importance of genotype-specific nutrient management and suggest that moderate N inputs (90–120&#xa0;kg&#xa0;ha⁻¹) combined with suitable varieties can greatly enhance maize productivity in the Guinea Savanna, promoting efficient use of resources.</p>