The present invention relates to a Smart Defect Calibration, Diagnosis, Sampling System and The Method Thereof for manufacturing fab is provided. The intelligent defect diagnosis method comprises: receiving pluralities of defect data, design layout data, analyzing the defect data, design layouts, by a Critical Area Analysis (CAA) system, wherein the analyzing step further contains the sub-steps: superposing the defect contour pattern and the design layout, performing CAA to identify a killer or non-killer defect based on the open or short failure probability, defects are classified as high, medium, low, or negligible risk defect based on the Killer Defect Index, defect signal parameters, selecting defect samples based on the defect classification data, selecting alarm defect and filtering false defect with pattern match with defect pattern library and frequent failure defect library, performing coordinate conversion and pattern match between image contour and design layout for coordinate correction, creating a CAA accuracy correction system and defect size calibration system by analyzing original defect size data and defect contour size from image analysis, evaluating the defect size using measurement uncertainty analysis with statistical analysis methods to reach the purposes of increasing CAA accuracy and Killer Defect identification rate.