Palmer amaranth (Amaranthus palmeri S. Watson) was first reported in Iowa in 2013 and has continued to spread across the state over the last decade. Amaranthus palmeri is widely recognized as one of the more economically important weeds in production agriculture. The presence of A. palmeri in Iowa is concerning as the species has evolved resistance to ten herbicide sites of action, however, no formal characterization has been conducted on Iowa populations. Therefore, herbicide assays were conducted on an A. palmeri population collected in Harrison County, IA, in 2023 (Southwest Palmer Amaranth [SWPA]) and a known herbicide-susceptible population collected from Nebraska in 2001 (Palmer Amaranth Susceptible [PAS]). The two populations were treated with preemergence and postemergence herbicides commonly used in Iowa. The treatments included preemergence applications of atrazine, metribuzin, and mesotrione and postemergence applications of atrazine, imazethapyr, glyphosate, lactofen, mesotrione, glufosinate, 2,4-D, and dicamba at 1× and 4× the labeled rates. Survival frequency of SWPA was >90% when treated postemergence with 1× rates of imazethapyr, atrazine, glyphosate, and mesotrione compared with ≤6% for PAS. Both SWPA and PAS had 0% survival when treated with lactofen, glufosinate, 2,4-D, and dicamba at the 1× or 4× rates. Plant population density reduction for SWPA was 53% and 40% in response to 1× rates of preemergence-applied mesotrione and atrazine, respectively. Metribuzin applied preemergence reduced SWPA plant population density by >90% at both rates. Dose–response experiments revealed the 50% effective doses (ED₅₀) of mesotrione, glyphosate, imazethapyr, and atrazine for SWPA were 9.5-,8.5-, 71-, and 40-fold greater than for PAS, respectively. The results confirm that SWPA is four-way multiple-herbicide resistant. Amaranthus palmeri infestations are likely to continue to spread within Iowa; therefore, diversified weed management programs that include early detection, rapid response, and effective multi-tactic management strategies will be required for control.