A novel series of functionalized synthetic substituted arylvinyl-1,2,4-trioxanes ( 8a-p ) has been prepared and assessed for in vitro antiplasmodial activity against chloroquine-resistant Pf INDO strain of Plasmodium falciparum using SYBR green-I fluorescence assay. Compounds 8g (IC 50 = 0.051 µ M; SI = 589.41) and 8m (IC 50 = 0.059 µ M; SI = 55.93) showed 11-fold and > 9-fold more potent antiplasmodial activity, respectively as compared to chloroquine (IC 50 = 0.546 µ M; SI = 36.63). In addition, 8a-p were also assessed for their in vitro anticancer activity against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Out of the sixteen synthesized arylvinyl-1,2,4-trioxanes, five ( 8a , 8h , 8l , 8m and 8o (IC 50 = 1.65 – 31.7 µ M; SI = 1.08-10.96) were found in vitro to be more active with superior selectivity than the reference compounds like artemisinin (IC 50 = 100 µ M), chloroquine (IC 50 = 100 µ M), as well as artesunic acid (IC 50 = 9.85 µ M; SI = 0.76) against (A549) lung cancer cell line. Compound 8l (IC 50 = 1.65 µ M; SI > 10), the most active anticancer compound of the series, was found to be > 60-fold more potent than parenteral drug artemisinin against (A549) lung cancer cell lines.© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.