Flumioxazin is commonly used in nursery production for PRE weed control. Container nursery producers are of the opinion that the granular formulation is less effective than the sprayable formulation. Under the hypothesis that the granular formulation may require more water for activation, an experiment was conducted to evaluate the interaction of flumioxazin formulation, rate, and activation moisture for PRE control of spotted spurge in a pine-bark substrate. Experiment consisted of a factorial arrangement of four experimental variables; flumioxazin formulation (granular and spray), and flumioxazin rate (0.28 and 0.42 kg ai ha−1), substrate moisture level at the time of application (dry, medium, and wet), and after-application irrigation level (a single irrigation at 0.6, 1.3, 2.5, and 5.1 cm). Treated pots were seeded with spotted spurge 2 d after the herbicide application, which was 1 d after the first irrigation. Control as indicated by spotted spurge counts and fresh weight was influenced only by flumioxazin rate and formulation. The sprayable formulation provided excellent control regardless of rate. Granular formulation was generally less effective, and additional activation moisture did not improve efficacy. Further studies were conducted with the granular formulation to determine the maximum separation distance between the spotted spurge seed and herbicide prills at which control is possible. Individual prills and spotted spurge seeds were placed on media surface at progressively increasing separation distances. Nonlinear regression of seedling survival data revealed that ≥99% control required a prill–seed separation of ≤5.2 mm. This prill–seed separation requirement is only marginally obtained with the current registered rate, i.e., 0.42 kg ai ha−1 or 168 kg product ha−1. The relationship between control and prill–seed separation distance cannot be manipulated by additional activation moisture. Inadequate contact between the spotted spurge seeds and the flumoioxazin-containing prills is likely the sole cause of inadequate control.