Successful screening campaigns depend on large and structurally diverse collections of compounds. In macrocycle screening, variation of the molecular scaffold is important for structural diversity, but so far it has been challenging to diversify this aspect in large combinatorial libraries. Here, we report the cyclization of peptides with two chemical bridges to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Application of this strategy to phage-encoded libraries allowed for the screening of an unprecedented structural diversity of macrocycles against plasma kallikrein, which is important in the swelling disorder hereditary angioedema. These libraries yielded inhibitors with remarkable binding properties (subnanomolar K, >1,000-fold selectivity) despite the small molecular mass (~1,200 Da). An interlaced bridge format characteristic of this strategy provided high proteolytic stability (t in plasma of >3 days), making double-bridged peptides potentially amenable to topical or oral delivery.