Malaria is a major global public health problem, and the alarming spread of drug resistance and limited number of effective drugs now available underline how important it is to discover new antimalarial compounds. An ethnopharmacological investigation was undertaken on Western Ghats plants traditionally used to treat malaria in India; 50 plants were very carefully selected from a total of 372 plants, and 200 extracts were prepared and tested for in vitro antiplasmodial activity alone and in combination with chloroquine (CQ) against CQ-resistant Plasmodium falciparum (strain MRC-Pf-43). In in vitro antiplasmodial activity, when plant extract alone is used, 29 extracts (or 14.5%) showed significant high in vitro antiplasmodial activity with IC50 values ranging from 3.96 to 4.85 mu g/ml, 53 extracts (or 26.5%) showed significant good in vitro antiplasmodial activity with IC50 values ranging from 5.02 to 9.87 mu g/ml, and 28 extracts (or 14%) showed significant moderate in vitro antiplasmodial activity with IC50 values ranging from 10.87 to 14 mu g/ml, respectively. In combination with CQ, 103 extracts (or 51.5%) showed significant synergistic in vitro antiplasmodial activities with synergistic factor values ranging from 1.03 to 1.92, and these activities were up to a fold higher with CQ, suggesting synergistic interactions of the two drugs. Our investigation has confirmed that above 62.1% of the plant extracts showed moderate to high in vitro antiplasmodial activity when used alone, and in combination with CQ, 55.7% of the extracts showed borderline to good synergistic activity.