Extensive areas of bare, compacted, and nutrient-poor soils hinder crop production in the Guinea Savannah Agro-ecological zone of Ghana. Resolving this challenge can be effected by developing sustainable land management strategies that can adequately improve soil nutrient status and enhance crop yield. Field studies were conducted to evaluate the productivity of cotton as affected by tillage practices, fertilizer rates and intercropping systems in the Guinea Savanna agroecology of Ghana, during the 2016 and 2017 cropping seasons. Treatments consisted of 2 tillage practices (ploughing and direct seeding [sole cotton]), 2 fertilizer application rates (54-30-30 kg/ha NPK and 0-0-0 kg/ha NPK) and 3 intercropping systems (sole cotton, cowpea intercrop and soybean intercrop) which were laid in split-split plot design with three replications. The tillage practices, fertilizer rates and the intercropping systems were respectively allocated as the main plot, sub-plot and sub-sub plot treatment respectively. Unlike the three-way interaction effect which did not significantly influence variation in growth, yield and yield components of cotton, the two-way interaction and the single factors were however influential. The combined impact of the NPK fertilizer application rate at 54-30-30 kg/ha and ploughing resulted in higher seed yield of cotton. Comparatively, seed yield of cotton was 35.78% higher when 54-30-30 kg/ha fertilizer rate (1.29 t/ha) was applied compared with 0-0-0 kg/ha fertilizer rate (0.61 t/ha). It is however recommended that resource-poor farmers in the Guinea Savannah agro-ecological zone of Ghana adopt to the use of 54-30-30 kg/ha fertilizer rate and ploughing for cotton seed yield maximization.