The weedy variety of Oryza sativa occurs in several rice cultivation areas reducing both grain yield and quality. Prevention and crop rotation are considered the basic means to reduce its presence. Weed control in sorghum is generally attained with atrazine. In this study, the efficacy of both chemical and mechanical methods for control, under different soil tillage conditions, of weedy rice and barnyardgrass during sorghum cultivation was evaluated with the aim to reduce the application rate of atrazine. In the case of chemical control, the atrazine rate (1000, 1500, 2000, 2500 and 3000 ga.i. ha−1) and application timing (pre- and post-emergence) were assessed. With the mechanical control method, the number of interventions (inter-row hoeing with sorghum at 3, 4–5 and 6–8 leaves) to avoid weed competition was determined. The effect of the tillage system on weed population was investigated comparing conventional (ploughing), minimum-tillage (disc harrowing) and sod seeding (no-tillage) in combination with pre- and post-emergence herbicide treatments. The results showed that efficient control of weedy rice and barnyardgrass was achieved in lowlands with sorghum in rotation with rice. Both chemical and mechanical methods of weed control in sorghum gave a level of efficiency higher than 60%. The application of atrazine was more efficient in pre-emergence application, rather than in post-emergence treatments, in all soil tillage systems tested. On both weed species, the most suitable application rate was the pre-emergence treatment with 1500 ga.i. ha−1, and the adoption of higher rates did not significantly increase the herbicidal efficacy. The adoption of two or three mechanical interventions resulted in sorghum yield higher than the chemical post-emergence application, and similar to the application of atrazine in pre-emergence. Higher yield results were in accordance to greater weed control, being obtained in the conventional tillage system.