To evaluate the weed control provided by various combinations of PRE applications of napropamide (Nap) and POST applications of mesotrione (Mes) in newly planted and 1-yr-old cranberry vines, six 2-yr experiments were conducted during 2009-2012. Three sites were treated in the year of planting plus the subsequent year (called “new plantings”) and three sites were treated in their second year of growth plus the subsequent year (called “second-year plantings”). Ten treatments, delivered in 3,735 L ha−1 water, were administered each year: Nap at 3.36 kg ai ha−1 applied once, twice, thrice or once followed by (fb) one application of Mes at 210 g ai ha−1; Nap at 5.04 kg ha−1applied once, twice or once fb one application of Mes at 210 g ha−1; Mes at 210 g ha−1 applied once or twice; and nontreated. At new planting sites, plots receiving treatments other than a single Nap application had less total weed biomass compared to nontreated plots. At second-year plantings, all herbicide-treated plots had less total weed biomass than nontreated plots; in addition, plots receiving Mes-only treatments had less total weed biomass than Nap-only treatments. Correlation analysis indicated that monocot biomass production was the primary positive predictor for total weed biomass. Herbicides did not adversely affect cranberry biomass production but overall vine colonization was poor for four of the six sites indicating that other factors, including cultivar choice, planting method, and water management, may play a larger role in rapid cranberry vine colonization than the suppression of initial weed biomass. Given the complementary range of efficacy for Nap and Mes, a combination PRE-POST herbicide program of a low rate of Nap fb Mes may be the most cost-beneficial program in many instances. If cost is a limiting factor, applying a single application of Mes to a new planting should be included as a component of cranberry bed establishment since this practice consistently resulted in significantly less initial weed biomass compared to areas left nontreated.