This study investigated the effect of conservation agriculture (CA) practices (e.g. no-tillage (NT) and maize-soybean (MS) intercrops) on the yield and profitability of maize and cotton within the first two years of a crop rotation system. A factorial design that compared two tillage practices (conventional tillage, CT and NT) and two cropping systems (sole maize, M and MS) was implemented on an experimental station in Northern Benin. All treatments were replicated thrice in 2022 and 2023. Soybean yield, maize grain yield and yield components, and seed-cotton yield and yield components were measured. Gross margin, labour productivity, and benefit:cost ratio were calculated, and a sensitivity analysis was done on the economic indicators under five scenarios (S0: gross margin calculation based on actual costs; S1: 30% higher fertiliser price; S2: 30% lower fertiliser price; S3 and S4, respectively: considering +/-1 standard deviation to the maize grain + soybean and seed-cotton yield). Tillage options and cropping systems significantly affected maize and cotton performance, but effects tended to vary between seasons. Treatment NT+MS produced the highest grain yield (4487 kg ha–1) and rain use efficiency (4.12 kg mm–1) in 2022, while CT+M produced the highest grain yield (3195 kg ha–1) and rain use efficiency (2.84 kg mm–1) in 2023. In the case of cotton, NT produced higher seed-cotton yield (1720 kg ha–1), boll number (7.38 bolls/plant), and rainfall use efficiency (1.56 kg mm–1) compared to CT in 2022. In 2023, cotton preceded by maize-soybean intercrops (NT+MS and CT+MS) produced significantly higher yield, aboveground and belowground biomass than cotton preceded by sole maize (NT+M and CT+M). For maize plus soybean, treatment NT+MS resulted in a significant increase in the gross margin, with an average of 582 US$ ha–1 with respect to CT+M under all scenarios in 2022, whereas CT+M and NT+MS attained a significantly higher maize/soybean gross margin in 2023. In the c