A three-year field study was conducted in Keiser, Arkansas to investigate the response of the naturally occurring weed flora, dominated by Palmer amaranth, under various combinations of 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide-based programs and crop rotation sequences. The first year, corn plots were established with three corn HPPD-based herbicide programs designed to represent a range of efficacies and selection pressures for resistance. The following two years, corn as monoculture or with soybean and/or cotton crops were included in rotation sequence for selected herbicide programs. Weed emergence, weed biomass, and soil seedbank were assessed through the entire experimental period. The results showed that crop rotation, especially a rotation sequence with corn followed by (fb) soybean fb cotton, and lowest risk herbicide program involving seven sites of action over the course of the entire crop rotation, was effective in reducing the emergence of naturally occurring weeds, including Palmer amaranth, prickly sida, morningglory species, and grass weeds (broadleaf signalgrass, large crabgrass, barnyardgrass, and johnsongrass) by 88.3, 57.5, 28.7, and 76.3% respectively Treatments without crop rotation (corn as monoculture for three consecutive years) and poor herbicide programs, with one site of action, increased weed emergence, notably Palmer amaranth and prickly sida by 73.5 and 74.1 respectively. The soil seedbank showed a similar trend to weed emergence. This study highlights the fact that reducing the weed seedbank cannot rely on one management practice but requires the use of a multi-tactic approach with various control methods. HPPD-inhibiting herbicide programs seem to be effective on Palmer amaranth when coupled with crop rotation and should be used with other best management practices.