Aim: The objective of this study was to determine the amount of twenty-three elemental impurities in Azithromycin API. A rapid, selective, precise, accurate and sensitive approach for detecting elemental impurities in Azithromycin API was developed and validated using ICP-MS. Background: Conventional analytical methods used in pharmacopoeias are less sensitive and accurate to detect heavy metal impurities. Materials and Methods: Test samples were prepared with microwave-supported acid digestion. Results: After several trials, a mixture of nitric acid, hydrochloric acid, and hydrogen peroxide (4 mL:1 mL:0.5 mL) was chosen with acceptable recovery. Conclusion: According to ICH and USP 233 guidelines, the proposed technique was validated for linearity, precision, accuracy, LOD, LOQ, and ruggedness. © 2023 Elsevier B.V., All rights reserved.