Marine natural products play critical roles in the chemical defense of many marine organisms and are essential, reputable sources of successful drug leads. Sixty-seven 14-membered resorcylic acid lactone derivatives 3– 27 and 30– 71 of the natural product zeaenol ( 1) isolated from the marine-derived fungus Cochliobolus lunatus were semisynthesized by chlorination, acylation, esterification, and acetalization in one to three steps. The structures of these new derivatives were established by HRESIMS and NMR techniques. All the compounds ( 1– 71) were evaluated for their antialgal and antiplasmodial activities. Among them, 14 compounds displayed antifouling activities against adhesion of the fouling diatoms. In particular, 9 and 34 exhibited strong and selective inhibitory effects against the diatoms Navicula laevissima and Navicula exigua (EC 50 = 6.67 and 8.55 μmol/L), respectively, which were similar in efficacy to those of the positive control SeaNine 211 (EC 50 = 2.90 and 9.74 μmol/L). More importantly, 38, 39, and 69– 71 showed potent antiplasmodial activities against Plasmodium falciparum with IC 50 values ranging from 3.54 to 9.72 μmol/L. Very interestingly, the five antiplasmodial derivatives displayed non-toxicity in the cytotoxicity assays and the zebrafish embryos model, thus, representing potential promising antiplasmodial drug agents. The preliminary structure–activity relationships indicated that biphenyl substituent at C-2, acetonide at positions C-5′ and C-6′, and tri- or tetra-substituted of acyl groups increased the antiplasmodial activity. Therefore, combining evaluation of chemical ecology with pharmacological models will be implemented as a systematic strategy, not only for environmentally friendly antifoulants but also for structurally novel drugs.