Thyroid cancer, a common malignancy, often involves the Rearranged During Transfection (RET) proto-oncogene, which drives tumorigenesis through the MAPK signalling cascade. Multikinase inhibitors such as vandetanib, regorafenib, and cabozantinib, which block the RET receptor, have been used for treatment but demonstrated limited efficacy due to nonspecific target interactions. Selpercatinib, a highly selective RET receptor tyrosine kinase (RTK) inhibitor, has emerged as a promising therapeutic agent. Initially developed for the treatment of non-small cell lung cancer, it is now employed in managing thyroid cancer, particularly the papillary thyroid cancer and medullary thyroid cancer variants, in both adults and pediatric patients above two years of age. Selpercatinib acts by inhibiting tyrosine kinase mutations, thereby preventing oncogene-driven proliferation. Its effectiveness is further supported by studies that have characterized the RET proto-oncogene expression profiles in normal versus cancerous tissues. Currently marketed under the brand name Retevmo, selpercatinib is available in tablet and capsule forms (40 mg and 80 mg). Typical side effects include musculoskeletal discomfort, diarrhea, headache, nausea, vomiting, fever (pyrexia), and bleeding, underscoring the need for therapeutic drug monitoring to optimize treatment outcomes. Analytical methodologies, such as Reverse Phase High-Performance Liquid Chromatography (RP–HPLC), Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS), and Nuclear Magnetic Resonance (NMR), have been developed and validated for determining selpercatinib and its degradation products. Additionally, bio-analytical methods for pharmacokinetic studies have been established and validated to ensure accurate drug monitoring and analysis.