We have employed a custom bioprospecing approach to identify cationic antimicrobial peptides from Komodo dragon plasma. Through these analyses we identified forty eight novel potential cationic antimicrobial peptides, with all but one of the identified peptides being derived from histone proteins. The antimicrobial effectiveness of eight of these peptides was evaluated against Pseudomonas aeruginosa 9027 and Staphylococcus aureus 25983, with seven peptides exhibiting antimicrobial activity against both microbes, and one only showing significant potency against Pseudomonas aeruginosa 9027. This study demonstrates the power and promise of our bioprospecting approach to CAMP discovery and it reveals the presence of a plethora of novel histone-derived antimicrobial peptides in the plasma of the dragon. These findings may have broader implications regarding the role that intact histones and histone-derived peptides play in defending the host from infection.