Giant ragweed is one of the most competitive annual broadleaf weeds in soybean production fields in the midwestern United States and eastern Canada because of its early emergence, rapid growth rate, high plasticity, and resistance to glyphosate and acetolactate synthase inhibitors. Therefore, early-season management of giant ragweed is critical to avoid yield loss. The objectives of this study were to evaluate control of glyphosate-resistant giant ragweed through the integration of preplant tillage or 2,4-D; PRE or early POST (EPOST) followed by (fb) late POST (LPOST) herbicide programs with or without preplant tillage or 2,4-D; and their effect on soybean injury and yield. A field study was conducted in 2013 and 2014 in David City, NE in a field infested with glyphosate-resistant giant ragweed. Preplant tillage or 2,4-D application provided > 90% control of glyphosate-resistant giant ragweed 14 d after preplant treatment. Giant ragweed control and biomass reduction were consistently > 90% with preplant tillage or 2,4-D fb sulfentrazone plus cloransulam PRE or glyphosate plus cloransulam EPOST fb glyphosate plus fomesafen or lactofen LPOST compared with ≤ 86% control with same treatments without preplant tillage or 2,4-D. PRE or EPOST fb LPOST herbicide programs preceded by preplant treatments resulted in giant ragweed density < 2 plants m−2 and soybean yield > 2,400 kg ha−1 compared with the density of ≥ 2 plants m−2 and soybean yield < 1,800 kg ha−1 under PRE or EPOST fb LPOST herbicide programs. The contrast analysis also indicated that preplant tillage or 2,4-D fb a PRE or POST program was more effective for giant ragweed management compared with PRE fb POST herbicide programs. Integration of preplant tillage would provide an alternative method for early-season control of giant ragweed; however, a follow up application of herbicides is needed for season-long control in soybean.