The in vitro susceptibility of Plasmodium falciparum to chloroquine (CQ), amodiaquine (AQ), monodesethylamodiaquine (mAQ) and piperaquine (PQP) antimalarial drugs was evaluated in 13 isolates from East New Britain Province of Papua New Guinea (PNG) using a colorimetric Plasmodium lactate dehydrogenase (LDH) assay. Of the 13 isolates assessed, 9 (69%) showed in vitro resistance to CQ with the concentration required to inhibit growth by 50% (IC50) ranging from 25 to 188.8 nM (geometric mean 118.7 nM). All parasites exhibited in vitro susceptibility to AQ, mAQ and PQP with their mean IC50s well below reported threshold values. Significant rank order positive correlations were observed between PQP and CQ (rs = 0.67, p <0.005) suggestive of potential in vitro cross-resistance between these two 4-aminoquinoline drugs. These results demonstrate the suitability of the enzyme-based LDH assay for assessing in vitro P. falciparum susceptibility and highlight the importance of in vitro assessment of antimalarial drugs in PNG in tandem with local therapeutic efficacy studies.