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Background: Drug use study in the community enables health authorities to understand pattern of drug utilization and its related aspects. This, in turn, can help to develop rational drug policies to be harmonized in accordance to the need of the community., Objective: The aim of this study was to assess drug use during acute illness by the general population in Tigray region, Northern Ethiopia., Method: A community based cross-sectional study was undertaken in April 2013 in Tigray Region, Ethiopia. A total of 1034 households were interviewed in the study. A multi-stage sampling technique was used to select households. Data were collected using a pre-tested structured questionnaire. Data were analyzed using descriptive statistics and bivariate and multivariate logistic regression model., Results: Out of 1000 households, 210(21%) reported an episode of acute illness. The prevalence of acute illnesses in rural areas 126(25%) (AOR = 1.83, 95% CI: 1.21-2.76) was significantly higher than that of urban areas 84(17%). Cough, runny nose, sore throat, earache, fever and headache added up to 155(52%) of all reported symptoms of acute illnesses. The majority of the patients 162 (77%) took modern medications for the managements of their diseases. Half 105(50%) of the consumed medications were antibiotics. The large proportions 173(83%) of medicines for acute illness were taken orally. The greater proportions 150(93%) of medications were prescribed by health professionals. Thirty-four households (21%) reported treatment discontinuation., Conclusion: The prevalence of acute illnesses in this study was found to be 21%. Acute illnesses were more common in rural areas than urban areas. Antibiotics were the most frequently used drugs for acute illnesses.