Maize production in low-yielding regions is influenced by climate variability, poor soil fertility, suboptimal agronomic practices, and biotic influences, among other limitations. Therefore, the assessment of yields to various management practices is, among others, critical for advancing site-specific measures for production enhancement. In this study, we conducted a multiseason calibration and evaluation of the DSSAT–CERES-Maize model to assess the maize yield response of two common cultivars grown in Trans Nzoia County in Kenya under various agricultural strategies, such as sowing dates, nitrogen fertilization, and water management. We then applied the Mann–Kendall (MK), and Sen’s Slope Estimator (SSE) tests to establish the yield trends and magnitudes of the different strategies. The evaluated model simulated long-term yields (1984–2021) and characterized production under various weather regimes. The model performed well in simulating the growth and development of the two cultivars, as indicated by the model evaluation results. The RMSE for yield was 333 and 239 kg ha−1 for H614 and KH600-23A, respectively, representing a relative error (RRMSE) of 8.1 and 5.1%. The management strategies assessment demonstrated significant feedback on sowing dates, nitrogen fertilization, and cultivars on maize yield. The sowing date conducted in mid-February under fertilization of 100 kg of nitrogen per hectare proved to be the best strategy for enhancing grain yields in the region. Under the optimum sowing dates and fertilization rate, the average yield for cultivar KH600-23A was 7.1% higher than that for H614. The MK and SSE tests revealed a significant (p < 0.05) modest downwards trend in the yield of the H614 cultivar compared to the KH600-23A. The eastern part of Trans Nzoia County demonstrated a consistent downwards trend for the vital yield enhancement strategies. Medium to high nitrogen levels revealed positive yield trends for more extensive coverage of the study area. Based on the results, we recommend the adoption of the KH600-23A cultivar which showed stability in yields under optimum nitrogen levels. Furthermore, we recommend measures that improve soil quality and structure in the western and northern parts, given the negative model response on maize yield in these areas. Knowledge of yield enhancement strategies and their spatial responses is of utmost importance for precision agricultural initiatives and optimization of maize production in Trans Nzoia County.