Metabolism of Plasmodium sp. produces toxic free heme and detoxifies it by dimerizing it into hemozoin. Most of antimalarial drugs including artemisinine inhibit the heme dimerization, and this pathway remains of considerable interest. Mass spectrometry is a highly selective tool to assess interaction of drugs with heme and detect active compounds showing this mechanism of action. We validated this strategy by monitoring adducts with 16 pure antimalarials like artemisinin and different quinolines, being determined: [Heme:Quinine] (m/z 940), [Heme:Quinacrine] (m/z 1015), [Heme:Amodiaquine] (m/z 994) and [Heme:Artemisinin] (m/z 898) among the others. We compared adducts stability by estimating the binding strength by in-source CID and demonstrated differences between drugs and the class of interaction (covalent or non covalent type). We implemented an online method to screen natural extracts by LC coupled to a micro-reactor, where isolated molecules react with heme before being monitored by MS. This method allowed the detection of several adducts with heme for Colombian plants: Symbolanthus pterocalyx, Clusia decusata and Monnina angustata and some of the most stable interactions were related with xanthone structures. The thermodynamic parameters of the binding of isolated molecules were compared to antimalarial drugs.