High-density polyethylene (HDPE) is widely used for dry-food packaging as a result of its excellent balance in cost, ease of processing and moisture barrier properties. The effects of molecular structure and rheological properties on crystalline morphology and barrier performance of HDPE blown films were investigated using three commercial HDPE resins with varying barrier performance. Based on the structure-barrier property relationships derived, a pathway for barrier resin design was proposed. New HDPE resins with optimized molecular structures were synthesized. Blown films of the new HDPE barrier resins exhibited excellent barrier performance and superior processibility.