Cancer cells must maintain molecular mechanisms relying on an energy trade-off between resistance and key functions to survive. PADI4 (peptidyl arginine deiminase 4) is an enzyme implicated in the conversion of arginine to citrulline (citrullination), that has been related to the development of several types of cancers and in numerous inflammatory routes. Salvianolic acid A (SAA) is a stilbenoid, obtained from the radix of Salvia miltiorrhiza , with several anti-cancer and anti-inflammatory features. In this work, we report and characterize the interaction between PADI4 and SAA. The binding reaction was followed by using several biophysical probes, namely fluorescence, isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR); the affinity constant was ∼600 nM (ITC). The enzyme binding to the C-terminal region of RING1B (E3 ubiquitin-protein ligase really interesting new gene 1 B), which is a substrate of PADI4, was altered in the presence of SAA, as shown by NMR. Colorimetric assays indicated that SAA was an activator of the citrullinating activity of PADI4. Moreover, the results in silico suggested that binding of SAA to the dimeric PADI4 occurred at the dimerization interface, and not at its active site, potentially stabilizing the dimeric, active form of the protein. The effect of SAA was shown to be cell-line-dependent, and its presence in glioblastoma cells hampered the binding between intact RING1B and the enzyme. Altogether, this work shows that PADI4 was capable of binding to SAA, at a novel site, and opens the venue to develop its use in modulating in vitro and in cellular assays the deimination processes.