The joint activity of mesotrione and atrazine can display synergistic effects on the control of both triazine-sensitive and site-of-action-based triazine-resistant (TR) broadleaf weeds. The first objective of this study was to evaluate a PRE application of atrazine followed by a POST application of mesotrione for potential interactions in both site-of-action-based TR redroot pigweed and metabolism-based atrazine-resistant (AR) velvetleaf. Results from these sequential experiments demonstrated that synergism was detected in reducing biomass of the TR redroot pigweed but not in the AR velvetleaf with metabolism-based resistance. The second objective was to evaluate the joint activity of mesotrione and atrazine in a tank-mix application in the AR velvetleaf biotype. Greenhouse studies with the AR biotype indicated that synergism resulted from a tank mix with a constant mesotrione rate of 3.2 g ai ha−1 in mixture with atrazine ranging from 126 to 13,440 g ai ha−1. Chlorophyll fluorescence imaging also revealed a synergistic interaction on the AR biotype when 3.2 g ha−1 of mesotrione was applied with 126 g ha−1 of atrazine beginning 36 h after treatment and persisting through 72 h.