Low inherent nitrogen (N), phosphorus (P), and potassium (K) contents of smallholder farms limit maize grain yield. Maize grain yield response to N, P, and K mineral fertilizer application and economically optimal rates for nitrogen (EOR N), phosphorus (EOR P), and potassium (EOR K) were evaluated on a Ferric Acrisol within the semi-deciduous forest zone of Ghana. The nutrient rates evaluated were N (0, 30, 60, 90, and 120 kg N ha −1), P (0, 30, 60, and 90 kg ha −1 P 2 O 5), and K (0, 30, 60 and 90 kg ha −1 K 2 O). The treatments were arranged in a randomized complete block with three replications using an incomplete factorial design. Nutrient responses were determined using asymptotic quadratic-plus plateau functions. The best nitrogen rate for all P and K levels was 60 kg ha −1 , which gave grain yield of 5 t ha −1. Nitrogen uptake, N agronomic and N recovery efficiencies peaked at 60 kg N ha −1 while N partial factor productivity declined with increasing N application rate. Cost to grain price ratios (CP) were 1.29, 1.65, and 1.65 for N, P, and K, respectively. The EOR N was 61 kg ha −1 , 32% less than the recommended 90 kg N ha −1 for maize production in the semi-deciduous forest zone of Ghana. Nitrogen application had the lowest CP ratio, making its application economically profitable than P and K. The findings suggest that the application of N at 61 kg N ha −1 to maize is economically profitable than at higher application rates. However, further studies should be conducted on farmers' fields to validate the results obtained.