Artemisinin‐based combination antimalarial therapy (ACTs), is still highly effective in uncomplicated falciparum malaria, however, there remain some concerns in relation to its safety and tolerability. Comorbid disease conditions may influence susceptibility to adverse drug reactions (ADRs) as the presence of multiple disease conditions may predisposes patients to ADRs due to the use of many medicines. There is therefore need to assess the impact of comorbidities on the ADR profile of malaria patients treated with ACTs. The study was carried out in health care facilities spread across Nigeria. From the database of over 10,000 patients recruited into an initial cohort, data for 1000 patients with comorbidities was extracted and matched with a control group of 1000 randomly selected patients with no comorbidity. There were 1105 adverse drug reactions in all, of which 66.2% were recorded in patients with comorbidity, and 34% are patients without comorbidity. The mean age of patients with comorbidities was 38.3 ± 17.5 years and 23.8 ± 17.2 for those without comorbidity. Out of the 979 patients with comorbidity, 36% were hypertensive, 2.2% hypertensive‐diabetes, 16.4% peptic ulcer disease, 10.4% HIV/AIDS, 4.4% diabetes and 4.3% were asthmatic. Patients with comorbidity were three times more likely to have adverse drug reaction than those without comorbidity (Odds ration = 2.96; 95% CI = 2.23–3.93). HIV/AIDS and osteoarthritis were significantly associated with development of adverse drug reactions. Probability was <0.0001. Age, weight, and height of patients were also found to be risk factor for development of adverse drug reactions.