The present invention relates to an oxygen isotope separation system and a method therefor. More specifically, the invention relates to a newly invented pressure-driven AGMD (Air Gap Membrane Distillation) system applied to a multi-stage membrane distillation cells which can produce an oxygen isotope effectively and economically, and a method therefor. The invention provides an oxygen isotope separation system including a number of Air Gap Membrane Distillation (AGMD) permeation cells connected in series to separate a feed into a product and a tail, wherein each of the AGMD cell is connected at a tail outlet with a reflux pump and at a product outlet, whereby the product from (i-1)th cell and the tail from (i+1)th cell are pumped as the feed into ith cell.