Meadowfoam seed meal (MSM), a by-product after oil extraction, has potential uses for crop growth enhancement or weed control. The herbicidal effect of MSM is the result of a secondary metabolite, glucosinolate glucolimnanthin (GLN). Field evaluations were conducted using concentrations of 3, 5, and 7% by weight and two forms (nonactivated and activated) of MSM applied as soil amendments. No injury was observed on lettuce transplanted 7 d after MSM incorporation in 2011. Activated MSM at 7% reduced weed emergence up to 71%. Lettuce leaf N content was at least 8.5-fold greater in MSM treatments compared to the untreated control. Greater soil nitrate levels correlated with greater weed biomass in MSM-amended plots. Isothiocyanate, a potent herbicidal compound, was detected in soil incorporated with 7% activated MSM. In 2012, 2.86 g m−2 of activated MSM, applied as a split or single dose, was evaluated for weed control efficacy and crop injury response. The split MSM application provided weed control similar to that from the single MSM application. The split and single MSM applications inhibited spiny sowthistle emergence more than 95% compared to the untreated control. A single application of activated MSM as a PRE soil amendment suppressed weeds and increased lettuce yield.