Development of ultra-sensitive, high specific and cost-effective nucleic acids (NAs) biosensors is critical for early diagnosis of cancer, genetic diseases and follows up response to treatment. Metal-organic frameworks (MOFs) as sensing materials underwent significant development in recent years due to their unique merits, such as structural diversity, tunable pore scale, large surface area, remarkable adsorption affinities, and good thermal stability. MOFs have shown potential contribution in nucleic acids biosensors research. Herein, a comprehensive overview on NAs biosensors state of the art based on MOFs has been discussed extensively, including different MOFs platforms sensing strategies (fluorescence, electrochemistry, electrochemiluminescence, and colorimetric techniques), their analytical performance and figures of merit in clinical diagnostics, with the future perspective in introducing MOFs in clinical laboratory diagnostics. Moreover, the different MOFs synthesis methods have been highlighted to serve as a guide for the researchers in selecting the appropriate platform that suits their research needs, and applications.