Intercropping cantaloupe and cotton can improve grower profits over traditional monoculture practices because crops share resources and production costs. However, developing effective programs to control weeds with herbicides that are safe to both crops can be challenging. Research was conducted to (1) identify herbicide systems to manage Palmer amaranth in cantaloupe–cotton intercropping production while minimizing crop injury, and (2) determine the profitability of cantaloupe–cotton intercropping. Ethalfluralin applied preplant did not injure cantaloupe or cotton, but Palmer amaranth was not controlled. The addition of fomesafen preplant improved Palmer amaranth control to at least 92% without injuring cotton, but cantaloupe necrosis and chlorosis of up to 20% was recorded. Halosulfuron-methyl was safely applied over cantaloupe, but its residual activity reduced cotton growth by 12% at 4 wk after planting; halosulfuron-methyl did not improve Palmer amaranth control beyond that noted with ethalfluralin plus fomesafen preplant. Intercropping systems that controlled Palmer amaranth at least 92% produced cantaloupe yields (25,760 to 25,890 fruit ha−1) similar to the weed-free monoculture system (24,120 fruit ha−1) but produced lint cotton yields that were 170 to 275 kg ha−1 less than the weed-free monoculture cotton system. Although cotton production was less in the intercropping system, the returns over variable costs with intercropping systems ($21,670 to 21,920 ha−1) exceeded those of cantaloupe monoculture ($18,070 ha−1) or cotton monoculture ($1,890 to $1,955 ha−1), as long as Palmer amaranth was controlled. Intercropping cantaloupe and cotton is an effective approach to share land resources and production inputs as well as to improve grower profitability and is being rapidly adopted by Georgia growers.