Establishment of alfalfa by interseeding it with corn planted for silage can enhance crop productivity but weed management is a challenge to adoption of the practice. Although a simple and effective approach to weed management would be to apply a glyphosate-based herbicide, concerns about herbicide resistance and limitations in available alfalfa varieties exist. Field experiments were conducted to compare the efficacy and selectivity of PRE, POST, and PRE followed by POST herbicide programs to a glyphosate-only strategy when interseeding alfalfa with corn. Experiment 1 compared PRE applications of acetochlor, mesotrione, S-metalochlor, metribuzin, and flumetsulam. Results indicate that acetochlor and metribuzin, and S-metalochlor used at a rate of 1.1 kg ai ha−1 were the most effective and selective PRE herbicides 4 wk after treatment (WAT), but each resulted in greater overall weed cover than glyphosate by 8 WAT. Experiment 2 evaluated applications of bentazon, bromoxynil, 2,4-DB, and mesotrione at early and late POST times. Several herbicides used POST exhibited similar effectiveness and selectivity as glyphosate, including early applications of bromoxynil (0.14 kg ai ha−1) and 2,4-DB (0.84 or 1.68 kg ai ha−1), as well as late applications of bromoxynil (0.42 kg ai ha−1), 2,4-DB (0.84 kg ai ha−1), and mesotrione (0.05 or 0.11 kg ai ha−1). A third experiment compared applications of acetochlor PRE, bromoxynil POST, and a combination of acetochlor PRE with bromoxynil POST. All treatments were effective and safe for use in this interseeded system, although interseeded alfalfa provided 65% to 70% weed suppression in corn planted for silage without any herbicide. Herbicide treatments had no observable impacts on corn and alfalfa yields, so weed management was likely of limited economic importance. However, weed competitiveness can vary based on several different factors including weed species, density, and site-specific factors, and so further investigations under different environments and conditions are needed.