Background In many developing countries including Ethiopia, maternal morbidity and mortality still pose a substantial burden and thus progress towards the fifth Millennium Development Goal (MDG) remains slow. Raising awareness of women about the danger signs of pregnancy and childbirth is the first essential step in accepting appropriate and timely referral to obstetric care. However, in Ethiopia little is known about the knowledge level of mothers about obstetric danger signs. The objective of this study was to assess the status of knowledge of danger signs of pregnancy and childbirth among mothers who gave birth in the past two years prior to the survey in Tsegedie district, Tigray regional state, Ethiopia. Methods A Community based cross-sectional study was conducted from November 20, 2012 to June 30, 2013 on a randomly selected sample of 485 women who had at least one delivery in the past two years. Multistage sampling technique was employed to select the study participants. A pre-tested structured questionnaire was used to collect quantitative data. Focus group discussion and in-depth interviews were utilized to supplement the Quantitative data. Bivariate and multivariate data analysis was performed using SPSS version 17.0 software. Result Four hundred eighty five mothers participated in the study making a response rate of 100%. Vaginal bleeding was the most commonly mentioned danger signs of pregnancy (49.1%) and childbirth (52.8%). Two hundred eighty five (58.8%) and 299 (61.6%) of respondents mentioned at least two danger signs of pregnancy and childbirth respectively. One hundred seventy (35.1%) and 154 (31.8%) of respondents didn't know any danger signs of pregnancy and childbirth respectively. Educational status of the mother, place of delivery and having functional radio were found to be independent predictors of knowledge of women about the danger signs of pregnancy and childbirth. Conclusion Educational status of the mother, place of delivery and having functional radio were independently associated with knowledge of women about obstetric danger signs. Thus, provision of information, education and communication targeting women, family and the general community on danger signs of pregnancy and childbirth and associated factors was recommended.