The exotic, invasive shrub European buckthorn (Rhamnus cathartica) is a major threat to natural areas in North America. While many publications describe buckthorn eradication methods, few compare the efficacy of different methods, and none are comprehensive. In this study, we tested the efficacy of 15 combinations of five commonly used herbicides and two physical interventions (cutting and girdling) on the regrowth of 317 buckthorn shrubs in northeastern Illinois. Treatments were performed randomly on plants with primary stems ≥3 cm, and effects on treated stems, untreated stems of multistemmed shrubs, and all stems were evaluated six months later. We found neither physical nor chemical methods alone to be optimal, but rather a combination of cutting or girdling with certain herbicides was best. We found Roundup Pro (Roundup), Stalker, and Tordon RTU (Tordon) to be more effective than either Garlon 4 or Brushmaster. Importantly, our data suggests that girdling or cutting of a single stem of multiple-stemmed buckthorn before using Roundup, Stalker, or Tordon usually results in the death of the entire shrub, thereby potentially saving a great deal of time and money. All herbicides were rated equally safe for human applicators by manufacturers, and required approximately equal time and effort to apply. Though Roundup was the most expensive of the three most effective herbicides, manufacturers' labels indicated that it is potentially safest for use in dry natural areas. However, none of the herbicides evaluated are appropriate for use in water, wetland areas, or in areas below mean high water marks.