The quantitative determination of xenobiotic compounds, as well as biotics in biological matrices, is generally described with the term bioanalysis. Due to the complexity of biofluids, in combination with the low concentration of the small molecules, their determination in biological matrices is a challenging procedure. Apart from the conventional solid-phase extraction, liquid-liquid extraction, protein precipitation, and direct injection approaches, nowadays, a plethora of microextraction and miniaturized extraction techniques have been reported. Furthermore, the development and evaluation of novel extraction adsorbents for sample preparation has become a popular research field. Metal-organic frameworks (MOFs) are novel materials composed of metal ions or clusters in coordination with organic linkers. Unequivocally, MOFs are gaining more and more attention in analytical chemistry due to their superior properties, including high surface area and tunability of pore size and functionality. This review discusses the utilization of MOFs in the sample preparation of biological samples for the green extraction of small organic molecules. Their common preparation and characterization strategies are discussed, while emphasis is given to their applications for green sample preparation.