Rush skeletonweed is an invasive weed in the winter wheat–fallow production regions of the inland Pacific Northwest. The objectives of this study were to determine the dose response of rush skeletonweed to picloram applied in the fall or spring of the fallow year with either a broadcast or weed-sensing sprayer, and to evaluate injury and grain yield in the subsequent winter wheat crop from these fallow treatments. Field studies were conducted between 2019 and 2022. Fall treatments were applied at one site in 2019, and one site in 2020. Spring treatments were applied at two sites in 2021. Four picloram herbicide rates (0, 140, 280, and 560 g ae ha−1), were applied with either a weed-sensing precision applicator or with a standard broadcast spray applicator. Rush skeletonweed densities in the wheat crop following fall-applied treatments declined with increasing picloram rates at both sites. Treatments applied with the weed-sensing sprayer achieved similar efficacy to broadcast treatments with an average of 37% and 26% of the broadcast rate applied. Spring-applied broadcast treatments resulted in reduced rush skeletonweed densities in wheat with increasing picloram rates. Picloram rate had no apparent effect on rush skeletonweed density when applied in the spring with a weed-sensing sprayer; however, the weed-sensing sprayer applied just 16% and 9% of the broadcast rate. Winter wheat grain yields were not reduced by fall picloram applications. Grain yields were not reduced by spring applications of picloram with the weed-sensing sprayer; however, grain yields were reduced by spring broadcast applications of picloram at both locations, and grain yields declined as the picloram rate increased. Applying picloram in the fall of the fallow phase with a weed-sensing sprayer provides effective and economical control of rush skeletonweed with a low risk for crop injury and yield loss in the following winter wheat crop.