Hairy fleabane and horseweed are pervasive weed species in agriculture. Glyphosate-resistant (GR) and glyphosate/paraquat– resistant (GPR) biotypes challenge current management strategies. These GR and GPR biotypes have non– target site resistance, which can confer resistance to herbicides with different sites of action (SOAs). This study’s objective was to characterize the response of GR, GPR, and glyphosate/paraquat– susceptible (GPS) biotypes of both weed species to herbicides with a different SOA. Whole-plant dose– response bioassays indicated a similar response among tested biotypes of both weed species to rimsulfuron, dicamba, hexazinone, glufosinate, flumioxazin, saflufenacil, or mesotrione. The hairy fleabane GR and GPR biotypes were 2.7- and 2.9-fold resistant to 2,4-D relative to the GPS biotype (GR50 766.7 g ai ha– 1), confirming 2,4-D resistance in hairy fleabane for the first time in California. The GR and GPR biotypes were not cross-resistant to dicamba. No differences in response to 2,4-D were observed among horseweed biotypes with a GR50 ranging from 150.2 to 277.4 g ai ha– 1. The GPR biotypes of both species were cross-resistant to diquat, with a 44.0-fold resistance in hairy fleabane (GR50 863.7 g ai ha– 1) and 15.6-fold resistance in horseweed (GR50 563.1 g ai ha– 1). The confirmation of multiple resistances to glyphosate, paraquat, and 2,4-D in hairy fleabane curtails herbicide SOA alternatives and jeopardizes resistance management strategies based on herbicide rotation and tank mixtures, underscoring the critical need for nonchemical weed control alternatives.