A roll-up door seal that may be monolithically formed from a single material of uniform density. The seal is sized and adapted to assemble to a standard roll-up door frame without a separate or dedicated frame structure. The seal provides redundant sealing surfaces, positioned to cooperate with both the door and door frame, which ensure an effective and durable fluid tight seal between the cargo space enclosed by the roll-up door and the ambient environment. The seal may be produced by extrusion from a flexible, weather resistant material such as EPDM, thereby providing a low cost solution for sealing roll-up doors having industry standard door frame constructions. The seal is firmly engageable with the door frame, such that the seal may be installed with little or no secondary fixation.