Cassava (Manihot esculenta Crantz) is an important staple food crop in Africa and South America, however, ubiquitous deleterious mutations may severely reduce its fitness. To evaluate these deleterious mutations in the cassava genome, we constructed a cassava haplotype map using deep sequencing from 241 diverse accessions and identified over 30 million segregating variants. While domestication modified starch and ketone metabolism pathways for human consumption, the concomitant bottleneck and clonal propagation resulted in a large proportion of fixed deleterious amino acid changes, raised the number of deleterious mutations by 24%, and shifted the mutational burden towards common variants. Deleterious mutations are ineffectively purged due to limited recombination in cassava genome. Recent breeding efforts maintained the yield by masking the harmful effects of deleterious mutations through shielding the most damaging recessive mutations in the heterozygous state, but unable to purge the load, which should be a key target for future cassava breeding.