Small molecules are essential for investigating the pharmacology of membrane proteins and remain the most common approach for therapeutically targeting them. However, most experimental small molecule screening methods require ligands containing radiolabels or fluorescent labels and often involve isolating proteins from their cellular environment. Additionally, most conventional screening methods are suited for identifying compounds with moderate to higher affinities (KD < 1 μM) and are less effective at detecting lower affinity compounds, such as weakly binding molecular fragments. To address these limitations, we demonstrated a proof-of-concept application of high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy with small molecules that bind the human A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor. Our approach leverages a streamlined workflow to prepare NMR samples with only milligrams of unpurified cell membranes containing ∼1 μM of A2AAR. Utilizing saturation transfer difference NMR, we identified bound small molecules from spectra recorded within minutes and further derived information on ligand binding poses without the need for detailed structure determination. After establishing optimal criteria for which the HRMAS approach is most sensitive, we leveraged our HRMAS approach to identify and characterize molecular fragments not previously known to be ligands of A2AAR. In molecular docking and simulations, we observed novel binding poses for these fragments, which revealed the potential to grow them into more complex ligands and confirmed HRMAS NMR as a valuable tool for lead compound identification in the context of fragment-based drug discovery.