Cotton (Gossypium hirsutum L.) is an important fiber crop in Pakistan with significant economic importance. Transgenic, insect-resistant cotton (carrying a gene from Bacillus thuringiensis (Bt)) was inducted in the cotton-based cropping systems of Pakistan during 2002, and is now sown in >90% of cotton fields in the country. However, concerns are rising that Bt cotton would decrease the productivity of winter crops (sown after cotton), leading to decreased system productivity. This two-year field study determined the impacts of transgenic (Bt) and non-transgenic (non-Bt) cotton genotypes on the productivities of winter crops (i.e., wheat, Egyptian clover, and canola), and the overall productivities of the cropping systems including these crops. Four cotton genotypes (two Bt and two non-Bt) and three winter crops (i.e., wheat, Egyptian clover, and canola) were included in the study. Nutrient availability was assessed after the harvest of cotton and winter crops. Similarly, the yield-related traits of cotton and winter crops were recorded at their harvest. The productivities of the winter crops were converted to net economic returns, and the overall economic returns of the cropping systems with winter crops were computed. The results revealed that Bt and non-Bt cotton genotypes significantly (p < 0.05) altered nutrient availability (N, P, K, B, Zn, and Fe). However, the yield-related attributes of winter crops were not affected by cotton genotypes, whereas the overall profitability of the cropping systems varied among the cotton genotypes. Economic analyses indicated that the Bt cotton–wheat cropping system was the most profitable, with a benefit–cost ratio of 1.55 in the semi-arid region of Pakistan. It is concluded that Bt cotton could be successfully inducted into the existing cropping systems of Pakistan without any decrease to the overall productivity of the cropping system.