The present study focuses on the method development and validation for detection of selective elemental impurities in Clarithromycin active pharmaceutical ingredient (API) using Inductively Coupled Plasma–Mass Spectrometry (ICP-MS). Elemental impurities, originating from catalysts, raw materials, or manufacturing processes, can adversely affect product safety and efficacy. Hence, a sensitive and precise analytical method was developed in accordance with ICH Q3D, USP <232>, and <233> guidelines. The optimized ICP-MS parameters ensured accurate quantification of 23 elemental impurities, including Cd, Pb, As, Hg, Co, Ni, V, Pd, Pt, Ir, Rh, Ru, Se, Ag, Mo, Sb, Cu, Sn, Cr, Ba, Li, Tl, and Au, in a single analytical run without the need for internal standards. The developed method was validated for linearity, accuracy, precision, specificity, limit of detection (LOD), and limit of quantification (LOQ). The method exhibited strong linear correlation (r² ≥ 0.99), recovery within 70–150%, and relative standard deviation (RSD) <20%, satisfying USP acceptance criteria. The Kinetic Energy Discrimination (KED) mode minimized polyatomic interference, improving signal stability and reducing analysis time. This validated method proved to be simple, rapid, rugged, cost-effective, and suitable for routine quality control analysis of Clarithromycin API to ensure compliance with elemental impurity regulations and pharmaceutical safety standards.