Production of food in resource-constrained environments that have poor inherent soil nutrition depends on tillage and cropping systems that provide high yields, preserve soil, water and biodiversity. This research was conducted in the Guinea savannah agroecology of Ghana, during the 2015-2016 cropping seasons to evaluate the impact of tillage and cropping systems on sustainable production of maize and soybean by resource-poor farmers. The experiment was a split-split plot design with four replications. The factors consisted of tillage system at three levels (plough, ripping and direct-seeding) laid out as main plots, fertilizer rate at three levels (0 kg/ha, half the recommended rate of 30-15-15 kg/ha and the recommended optimum rate of 60-30-30 kg/ha NPK) laid as sub-plots and cropping system at two levels (sole maize, maize-soybean intercrop) laid on the sub-sub plot. Apart from leaf area that had significant three-way interaction of tillage, cropping system and fertilizer rate (p < 0.05), all other growth parameters were affected by either two factor interaction or a sole factor. Grain yield of maize was significantly influenced by sole maize and fertilizer rate with highest yield occurring under the full rate (3.4 t/ha) compared with the half rate (2.7 t/ha), amounting to yield difference of about 700 kg/ha. Yield of soybean under the integrated production was affected by interaction of tillage system and fertilizer rate. Highest soybean yield (1.4 t/ha) was recorded under the ploughed condition at the full rate of fertilizer application. Though sole maize, ploughed and with full rate of fertilizer application, gave similar benefit/cost ratio as that of the integrated production with half rate of fertilizer application, the intercropped system with half fertilizer rate resulted in 45% more increases in profit compared to the sole production with full fertilizer rate. Integrated production of maize and soybean, with half the recommended rate of NPK (30-15-15 kg/ha) is therefore recommended to resource-poor farmers in northern Ghana.