The aim of this work was to demonstrate and to evaluate the analytical performance of combined falling drop/open port sampling interface (OPSI) system as a simple non-contact, no-carryover, automated system for flow injection analysis with mass spectrometry. The falling sample drops were introduced into the OPSI using a widely available autosampler platform utilizing low cost disposable pipette tips and conventional disposable microtiter well plates. The volume of the drops that fell onto the OPSI was in the 6-15 μL range with an injected sample volume of several hundred nanoliters. Sample drop height, positioning of the internal capillary on the sampling end of the probe and carrier solvent flow rate were optimized for maximum signal. Sample throughput, signal reproducibility, matrix effects and quantitative analysis capability of the system were established using the drug molecule propranolol and its isotope labeled internal standard in water, unprocessed river water and two commercially available buffer matrices. A sample-to-sample of ~45 s throughput with an ~4.5 s base-to-base flow injection peak profile was obtained in these experiments. In addition, quantitation with minimally processed rat plasma samples was demonstrated with three different statin drugs (atorvastatin, rosuvastatin and fluvastatin). Direct characterization capability of unprocessed samples was demonstrated by the analysis of neat vegetable oils. Employing the autosampler system for spatially resolved liquid extraction surface sampling exemplified by the analysis of a propranolol and its hydroxypropranolol glucuronide phase II metabolites from a rat thin tissue section was also illustrated.