SUMMARY: Analysing protein structure similarities is an important step in protein engineering and drug discovery. Methodologies that are more advanced than simple RMSD are available but often require extensive mathematical or computational knowledge for implementation. Grouping and optimizing such tools in an efficient open-source library increases accessibility and encourages the adoption of more advanced metrics. Melodia is a Python library with a complete set of components devised for describing, comparing and analysing the shape of protein structures using differential geometry of 3D curves and knot theory. It can generate robust geometric descriptors for thousands of shapes in just a few minutes. Those descriptors are more sensitive to structural feature variation than RMSD deviation. Melodia also incorporates sequence structural annotation and 3D visualizations. AVAILABILITY AND IMPLEMENTATION: Melodia is an open-source Python library freely available on https://github.com/rwmontalvao/Melodia_py, along with interactive Jupyter Notebook tutorials.