Two antimicrobial peptides (AMPs) of marine origin, tachyplesin from the Japanese horseshoe crab, Tachypleus tridentatus, and pleurocidin-amide from the winter flounder, Pseudopleuronectes americanus, were tested for their potential effectiveness in disease treatment in oyster aquaculture. Tachyplesin had a greater antimicrobial effect than pleurocidin-amide against a range of gram-positive and gram-negative bacteria, with minimum inhibitor concentrations in the range of 0.625 to 5 μg mL⁻¹. Tachyplesin (50 μg mL⁻¹) was also more effective than pleurocidin-amide (250 μg mL⁻¹) against the oyster protozoan parasite Perkinsus marinus, reducing its viability to 9% versus 22% in vitro. Both peptides were unaffected by variations in pH and salinity that would be encountered in marine culture conditions. Candidate algal and yeast for expression and feed-based delivery of recombinant AMPs were largely unaffected by tachyplesin and pleurocidin at concentrations that inhibited bacterial growth but were sensitive to concentrations that reduced the viability of P. marinus. Several proteases, including those of oyster and parasitic origin, decreased AMP activity, but tachyplesin was affected to a much lesser degree than pleurocidin-amide. Coincubation of homogenates from oyster digestive tissues with tachyplesin and pleurocidin-amide was found to reduce the abundance of colony forming units in the tissue. Tachyplesin was more effective against gram-negative bacteria present in oyster tissues, whereas pleurocidin-amide was more effective against gram-positive bacteria. Tachyplesin was considered a better candidate than pleurocidin-amide for feed-based delivery applications in oyster aquaculture.