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Background   Plasmodium falciparum  resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) has historically posed a major threat to malaria control throughout the world. The country of Angola officially replaced CQ with artemisinin-based combination therapy (ACT) as a first-line treatment in 2006, but malaria cases and deaths have recently been rising. Many classic resistance mutations are relevant for the efficacy of currently available drugs, making it important to continue monitoring their frequency in Angola.    Methods   Plasmodium falciparum  DNA was sampled from the blood of 50 hospital patients in Cabinda, Angola from October-December of 2018. Each infection was genotyped for 13 alleles in the genes  crt ,  mdr1 ,  dhps ,  dhfr , and  kelch13,  which are collectively involved in resistance to six common anti-malarials. To compare frequency patterns over time,  P. falciparum  genotype data were also collated from studies published from across Angola in the last two decades.    Results  The two most important alleles for CQ resistance,  crt  76T and  mdr1  86Y, were found at respective frequencies of 71.4% and 6.5%. Historical data suggest that  mdr1  N86 has been steadily replacing 86Y throughout Angola in the last decade, while the frequency of  crt  76T has been more variable across studies. Over a third of new samples from Cabinda were ‘quintuple mutants’ for SP resistance in  dhfr / dhps , with a sixth mutation at  dhps  A581G present at 9.6% frequency. The markers  dhfr  51I,  dhfr  108N, and  dhps  437G have been nearly fixed in Angola since the early 2000s, whereas  dhfr  59R may have risen to high frequency more recently. Finally, no non-synonymous polymorphisms were detected in  kelch13 , which is involved in artemisinin resistance in Southeast Asia.    Conclusions  Genetic markers of  P. falciparum  resistance to CQ are likely declining in frequency in Angola, consistent with the official discontinuation of CQ in 2006. The high frequency of multiple genetic markers of SP resistance is consistent with the continued public and private use of SP. In the future, more complete haplotype data from  mdr1 ,  dhfr , and  dhps  will be critical for understanding the changing efficacy of multiple anti-malarial drugs. These data can be used to support effective drug policy decisions in Angola.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12936-021-03713-2.

Historical trends and new surveillance of Plasmodium falciparum drug resistance markers in Angola