Calixarenes are a structurally versatile class of macrocyclic compounds that exhibit broad functionality across pharmaceutical, analytical, industrial, and environmental domains. Their conformational flexibility and functionalize upper and lower rims facilitate selective host–guest interactions, enabling their use in targeted drug delivery systems with demonstrated antiviral, antibacterial, antifungal, and anticancer efficacy. In analytical chemistry, calixarene-based sensors have been integrated into colorimetric, fluorometric, potentiometric, and voltammetric platforms, offering high selectivity and low detection limits for analytes such as metal ions, nucleotides, and neurotransmitters. Advances in medical imaging have leveraged calixarene derivatives to enhance MRI contrast and specificity. Their strong chelating capabilities and environmental stability support their application in water purification and soil remediation. Commercial developments, including green leather tanning agents, anti-corrosion coatings, and COVID-19-era antiviral coatings, highlight their real-world potential. Furthermore, computational and AI-driven molecular modeling approaches have facilitated rational calixarene design by predicting binding affinities, dynamic conformations, and interaction energies. While promising, considerations such as low intrinsic solubility, scale-up limitations, and dose-dependent cytotoxicity require further exploration for clinical translation. This review provides a comprehensive evaluation of calixarenes, emphasizing their evolving role as supramolecular platforms in next-generation scientific and industrial innovations. © 2025 Elsevier B.V., All rights reserved.