Proso millet is an important short-season summer cereal in western Nebraska, southeast Wyoming, and eastern Colorado. The objective of this study was to evaluate proso millet tolerance to saflufenacil applied early preplant (EPP) or PRE. Field studies were conducted in Lingle, WY and Sidney, NE in 2008 and 2009. A dose–response study was conducted in the greenhouse at the University of Wyoming in Laramie, WY to determine proso millet cultivar response to saflufenacil applied at six rates from 0 to 400 g ai ha−1. In the field, saflufenacil was applied EPP and PRE at 50 and 100 g ha−1. Proso millet stands were reduced by an average of 33 and 23% by PRE and EPP treatments compared with the nontreated check; however, proso seed yields were not affected by saflufenacil timing or rate. In the greenhouse, ‘Panhandle’ and ‘Dawn’ exhibited less tolerance to saflufenacil than ‘Sunrise’, the cultivar used in the field studies.