Perennial pepperweed is an invasive weed spreading rapidly throughout a wide range of habitats in the western United States. This study was designed to test whether integrating early season mowing with a systemic herbicide application would improve the control of perennial pepperweed. Experiments were conducted within three different environments including high desert, roadside, and floodplain areas. In treatments not mowed, chlorsulfuron at 0.104 kg ai/ha reduced perennial pepperweed biomass and density by 100%, whereas applications of 2,4-D at 2.11 kg ae/ha and glyphosate at 3.33 kg ae/ha were inconsistent and did not provide effective control. Mowing alone did not reduce perennial pepperweed biomass or density the following year, but mowing followed by application of a herbicide treatment to resprouting plants reduced biomass at all three sites compared with nonmowed treatments including herbicides. Among combinations of mowing and herbicides, chlorsulfuron at 0.052 kg/ha reduced perennial pepperweed biomass by >99% at all three sites, and glyphosate at 3.33 kg/ha reduced biomass by ≥80% at two sites 1 yr after applications. The effectiveness of glyphosate at 3.33 kg/ha in combination with mowing provides land managers with a valuable control option for perennial pepperweed in wetland or riparian areas where chlorsulfuron is not registered for use.