Indaziflam is a PRE herbicide for control of annual grass and broadleaf weeds in numerous settings, including managed roadsides, railroads, and noncroplands. There is a need for new and improved PRE herbicides for herbaceous vegetation management along roadsides; however, off-target crop injury via spray drift is a concern because of the close proximity of roadside applications to the wide array of crops grown throughout the southeastern United States where indaziflam is used. Greenhouse research was conducted to evaluate the effect of PRE and POST simulated indaziflam spray drift rates on the growth of cotton, bell pepper, soybean, squash, tobacco, and tomato. Simulated indaziflam spray drift rates were 100, 20, 10, 5, or 2.5% of a 73 g ai ha−1 application rate, whereas other herbicide treatments included for comparative purposes were applied at 10% of a typical North Carolina roadside vegetation management application rate. These included sulfometuron (4 g ai ha−1), aminocyclopyrachlor + metsulfuron (11 + 3.5 g ai ha−1), clopyralid + triclopyr (21 + 63 g ai ha−1), or aminopyralid (12 g ai ha−1). In general, plant growth responses varied among herbicides and application timings. Across all evaluated parameters, indaziflam at the 10% simulated drift rate adversely effected plant growth similarly or less than all other herbicides when applied PRE (squash and tomato), POST (bell pepper and soybean), and PRE or POST (cotton and tobacco). No clear trends were observed regarding indaziflam application timing, as PRE squash and tomato, and POST bell pepper and soybean applications were safer than their respective alternative timing, and no significant differences were detected between timings on cotton or tobacco. Across application timings, plant susceptibility to indaziflam-simulated spray drift rates ranked cotton < tobacco < tomato < squash < pepper < soybean. Finally, it should be noted that the lowest simulated indaziflam drift rate (2.5%) caused greater than 20% root mass reduction on cotton (POST), bell pepper (PRE and POST), soybean (PRE and POST), squash (PRE), and tomato (POST). Although this research supports indaziflam use along roadsides, it still poses an off-target plant injury risk. Future research should evaluate techniques to minimize spray drift from roadside pesticide applications.