Total vegetation control (TVC) is an essential management practice to eliminate all vegetation for the purpose of protecting infrastructure, people, or natural resources on sites where vegetation poses major fire, visibility, and infrastructure risks. TVC is implemented on sites such as railroads, power substations, airports, roadsides, and oil and gas facilities. Current research has identified that tank-mixing two effective mechanisms of action is a superior resistance management strategy compared to rotating mechanisms of action; however, effective tank mixes for TVC have not been thoroughly evaluated. A field experiment was conducted from 2013 to 2014 at five sites in Colorado to compare 32 treatment combinations to two industry standards for TVC. Research objectives were (1) to identify herbicide tank-mix combinations for TVC with multiple effective mechanisms of action for resistance management, (2) to evaluate lower use rate alternatives to minimize nontarget impacts, and (3) to determine the efficacy of fall versus spring application timings. Seven treatments were identified as top-ranking treatments, averaging 96% bare-ground (BG) across five sites and two application timings. Four out of the seven top-ranked treatments included aminocyclopyrachlor, chlorsulfuron, and indaziflam. The industry standard diuron plus imazapyr was in the top ranking, whereas the other industry standard bromacil plus diuron performed inconsistently across sites. Probability modeling was used to predict the probability of achieving 97% or 100% BG with various treatment combinations. The combination of aminocyclopyrachlor, chlorsulfuron, indaziflam, and imazapyr had the highest predicted BG probability, with 88% predicted probability of achieving 100% BG, compared to 67% and 52% predicted probabilities for the industry standards diuron plus imazapyr and bromacil plus diuron, respectively. In three of the five sites, fall applications outperformed the same treatments applied in the spring. Several top-ranking treatments represent newer, lower use rate herbicide combinations that provide multiple mechanisms of action to manage herbicide-resistant weeds and minimize nontarget impacts.