Owing to the lack of effective POST herbicide options, producers typically rely on nicosulfuron as the main POST grass herbicide in sweet corn production systems. In 2019, a Wisconsin sweet corn producer reported fall panicum control escapes after spraying nicosulfuron. Seeds from mature plants were collected to (1) measure fall panicum response to acetolactate synthase (ALS)-inhibiting herbicides, (2) elucidate the resistance mechanism, and (3) evaluate its response to alternative POST herbicides. Greenhouse and laboratory investigations were conducted to assess fall panicum response to ALS-inhibiting herbicides and elucidate the resistance mechanism. Dose–response results showed that fall panicum was highly resistant to nicosulfuron with a resistance ratio of >12.9-fold (survived rates >254 g ai ha−1, or 8× the field label rate). Molecular and genetic studies indicated that there are multiple ALS gene copies in fall panicum and that resistance was due to a mutation in one copy, resulting in an Asp-376-Glu amino acid substitution. Additional greenhouse experiments indicate that clethodim (105 g ai ha−1), quizalofop-p-ethyl (70 g ae ha−1), glyphosate (864 g ae ha−1), and glufosinate (650 g ai ha−1) are effective POST options to manage the ALS-resistant fall panicum (>90.0% control and 96.8% biomass reduction) in rotational years. The 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides isoxaflutole (105 g ai ha−1), mesotrione (105 g ai ha−1), tembotrione (92 g ai ha−1), and tolpyralate (39 g ai ha−1) did not provide effective POST fall panicum control. Because these herbicides are commonly used for POST weed control in sweet corn, more investigations are required to evaluate combinations of HPPD-inhibiting herbicides with herbicides from other sites of action for POST fall panicum control. Herein we confirm the first case of herbicide resistance in fall panicum in the United States.