Tiafenacil is registered in the United States for use in annual crops such as corn and soybean, but not on orchard crops. Field studies were conducted to determine orchard crop safety and efficacy of tiafenacil on important California orchard weeds. To evaluate crop safety, tiafenacil was applied at 74, 148, and 222 g ai ha−1 alone and with 38 g ai ha−1 of tolpyralate three times per year at the base of almond, pistachio, prune, and walnut trees. The first treatment was applied 2 mo after the trees had been transplanted. In all four tree crop experiments, treatments were applied once in May 2020, then three times again during the winter of 2021 and 2022 at 21-d treatment intervals. There were no visual foliar injury symptoms or treatment-related effects on tree trunk diameter change even at the highest tested rate of tiafenacil applied seven times over three growing seasons. In a separate study of weed control, in most instances, tiafenacil applied at 12 g ai ha−1 performed similarly to that of tiafenacil plus glufosinate. Control of glyphosate-resistant hairy fleabane with tiafenacil applied alone at 25 g ai ha−1 was 65% by 14 d after treatment. Tiafenacil applied at 50 g ai ha−1 to hairy fleabane performed similarly to glufosinate plus glyphosate. In a greenhouse study, tiafenacil applied at 12 g ha−1 provided 95% to 100% control of barnyardgrass and junglerice, and there was no significant difference between tiafenacil applied alone or with glufosinate. Saflufenacil applied alone or in a mixture with glufosinate was not as effective as the tiafenacil treatments for grass weed control. Based on experiments conducted over three growing seasons in four tree fruit and tree nut crops, tiafenacil crop safety appeared to be acceptable even at up to 2- or 3-fold the expected use rate.