Sesame is an oil seed crop with great economic value. However, the production of this crop has been limited by weed competition, which prompted a field experiment during the 2021 cropping season in two locations: Teaching and Research Farm, Kwara State University, Malete, and National Centre for Agricultural Mechanization (NCAM), Idofian, Ilorin, Kwara, Nigeria. The aim was to determine the treatment combinations of sowing methods and herbicide mixtures for the effective management of weeds and for increasing sesame productivity in the southern Guinea savanna of Nigeria. The experiment consisted of twenty treatments comprising two sowing methods (dibbling and drilling) and ten weed control methods. Results showed that all the weed control methods reduced weed dry matter (67.15–186.20 and 42.00–92.45 g/m2) than the weedy check (291.55 and 155.55 g/m2) at Malete and NCAM, respectively. They also reduced the weed density (48.40–68.45 and 34.00–50.00/m2) compared to the weedy check (103.60 and 73.15 g/m2) at Malete and NCAM, respectively, from 6 to 12 weeks after planting (WAP). Dibbling (85.15 and 48.81 m2) proved superior to the drilling method (172.42 and 51.58/m2) for the management of weeds from 6–12 WAP and for promoting higher crop yield (dibbling: 78.90 and 422.70 kg/ha; drilling: 37.50 and 326.80 kg/ha) in Malete and NCAM, respectively. The treatment combinations with the highest gross margin were hoeing twice at 3 and 6 WAP × dibbling ($ -191.15 and $ 318.57), pendimethalin (P) + diuron (D) at 0.5 + 0.5 kg a.i./ha ($ -199.88 and $ 182.43), 2.0 + 1.5 × dibbling ($ -273.59 and $ 156.65) and butachlor (B) + diuron (D) at 1.5 + 1.0 kg a.i./ha × drilling ($ -269.59 and $ 177.38) at Malete and NCAM, respectively. Therefore, it is recommended that the dibbling sowing method at a spacing of 30 cm × 30 cm and thinned to 3 plants/stand integrated with herbicide mixtures of pendimethalin at 0.5 + 0.5 kg a.i./ha is recommended as an alternative to hoe weeding for effective weed control, higher yield of sesame, and economic returns.