In this work, we synthesized highly water-dispersible multiwalled carbon nanotubes@polydopamine (MWCNTs@PDA) core-shell composites by a facile in situ oxidative polymerization. The composites were successfully applied as a novel matrix for the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of various water-soluble small molecule compounds. It was found that MWCNTs@PDA composites have a higher sensitivity and peak intensities for small molecules detection.