Successful weed management, particularly use of chemical control, is very important for commercial lettuce production on organic soils in the Everglades Agricultural Area in south Florida. Field experiments were conducted in 2016 and 2017 to determine the efficacy of herbicides (pronamide, bensulide, imazethapyr, or oxyfluorfen) applied preemergence (PRE) either alone or followed by a postemergence (POST) application of imazethapyr for weed control and lettuce (romaine and iceberg) yield. Preemergence-applied oxyfluorfen (0.56 kg ha−1) resulted in significant lettuce injury, including stand loss, while PRE applications of pronamide (4.44 kg ha−1), bensulide (5.6 and 10.1 kg ha−1), or imazethapyr (0.035 g ha−1) resulted in transient lettuce injury and no significant stand loss. Similarly, PRE-applied pronamide, bensulide, and imazethapyr followed by POST-applied imazethapyr did not result in significant lettuce stand loss or injury. When contrasted as a group, PRE-applied herbicides followed by a POST application of imazethapyr provided better spiny amaranth and common lambsquarters control compared with PRE-applied herbicides or POST-applied imazethapyr-only treatments. Lettuce yield was highest with PRE herbicides followed by POST imazethapyr compared with PRE herbicides or POST-applied imazethapyr-only treatments, indicating a yield benefit of having a PRE followed by POST herbicide weed control program in lettuce grown on organic soils. However, oxyfluorfen is not an option for lettuce on organic soils because of unacceptable stand reduction and crop injury. Whether to apply pronamide, bensulide, or imazethapyr PRE followed by a POST application of imazethapyr for broadleaf weed control in lettuce on organic soils depends on the species present, cost, and ease of application.