In continuation of a search for new antiprotozoal agents from plants of the family Asteraceae, Tarchonanthus camphoratus and Schkuhria pinnata have been investigated. By following the promising in vitro activity of the dichloromethane extracts from their aerial parts, bioassay-guided chromatographic isolation yielded two known sesquiterpene lactones (1 and 2) from T. camphoratus and 20 known compounds of this type from S. pinnata. From the latter, a new eudesmanolide, (1R*,5S*,6R*,7R*,8R*,10R*)-1-hydroxy-8-[5″-hydroxy-4'-(2″-hydroxyisovaleroyloxy)tigloyloxy]-3-oxoeudesma-11(13)-en-6,12-olide (3), and two new germacranolides, 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)costunolide (14) and 1(10)-epoxy-3β-hydroxy-8β-[5'-hydroxy-4'-(2″-hydroxyisovaleroyloxy)tigloyloxy]costunolide (16), were obtained. Additionally, the flavonoid pectolinarigenin (24) and 3-hydroxy-4,5-dimethoxybenzenepropanol (25) were also isolated from S. pinnata. The compounds were characterized by analysis of 1D and 2D NMR spectroscopic and HR/MS data. In vitro antitrypanosomal activity and cytotoxicity against mammalian cells (L6 cell line) were evaluated for all the compounds. Santhemoidin A (13) and 3β-(2″-hydroxyisovaleroyloxy)-8β-(3-furoyloxy)costunolide (14) were the most active compounds found in this study, with IC50 values of 0.10 and 0.13 μM against Trypanosoma brucei rhodesiense trypomastigotes and selectivity indices of 20.5 and 29.7, respectively.