Herbicide-resistant Italian ryegrass [Lolium perenne L. spp. multiflorum (Lam.) Husnot] is a significant problem in multiple cropping systems because of its rapid growth, open pollination, prolific seed production, and multiple cases of resistance worldwide, except to protoporphyrinogen oxidase (PPO) inhibitors. This research evaluated tiafenacil, a new PPO inhibitor, in mixtures with glutamine synthetase or acetyl-CoA carboxylase (ACCase)-inhibiting herbicides to manage resistant L. multiflorum populations. Tiafenacil efficacy against L. multiflorum was growth stage-dependent, with increased efficacy at earlier stages in greenhouse studies. The LD90 was 41.06 g ai ha-1 at BBCH23, and increased to 9.0-fold at BBCH33. Field studies indicated that changes in carrier volume did not affect tiafenacil’s efficacy; the highest tested rate of tiafenacil (75 g ai ha-1) reduced L. multiflorum inflorescence weight by 50-90%. Mixtures of tiafenacil and glufosinate (1,150 g ai ha-1) improved L. multiflorum control (+24-43%) and reduced inflorescence weight (+15-34%), particularly at the highest tested rates (50 and 75 g ai ha-1), suggesting synergistic effects based on Colby’s test. Tiafenacil with ACCase inhibitors improved L. multiflorum control (+19-49%) and inflorescence weight reduction (+8-13%). These mixtures exhibited an additive effect when combined with fluazifop and a synergistic effect with clethodim. Herbicide mixtures and application strategies are critical to effective L. multiflorum management. Tiafenacil, especially when used with glufosinate or ACCase inhibitors, offers an effective solution to L. multiflorum management and is a strategic tool against herbicide resistance, as resistance to PPO inhibitors has not evolved. Further research should assess practices to ensure the long-term viability of these mixtures for resistance management.