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Decline in soil fertility is one of the major constraints to sustainable crop production and profitability. To meet the increasing demand for the growing population the issue of low soil fertility needs to be addressed. An on-farm experiment was established to evaluate the effect of interaction between NPK fertilizers and minimum tillage on soil fertility, maize crop yield and on farm profit margins. The field trials were set up in a split-plot design organized in a randomized complete block design in 28 farmers' fields. Application of all the three macronutrients i.e. NPK had the highest and significant (P < 0.0001) yields relative to treatments, where any of the three nutrients was omitted. Maize grain yield increased by over 150% with NPK, NP and NK application in all the three cropping seasons over the control. Grain losses with the omission of a single nutrient were highest with N (2.06, 2.40 & 2.42 t ha-1) followed by P (0.8, 0.59 & 0.43 t ha-1) in the short rain 2014 (SR2014), long rains 2015 (LR2015) and SR2015 seasons, respectively. Conservation agriculture recorded a significant (P < 0.0007) increase in P over the three seasons. There was significantly higher K in the soil within the NP and PK treatments and in the conservation agriculture compared to the conventional agriculture systems. Compared with conventional tillage, the benefit to cost ratio was higher by 3 and 5% under minimum tillage during the LR2015 and SR2015 seasons, respectively. Total variable cost was 4 and 2% higher under conventional tillage compared to minimum tillage during the LR2015 and SR2015 seasons, respectively. Treatments with N and conservation agriculture were the most profitable. A combined use of conservation agriculture and all the three macro-nutrients (NPK) is the best bet for increasing, maize crop yield and associated return on investment.