Background The clinical learning environment is important to achieve the defined learning outcomes of the program, however nurse students face a multitude of challenges during their clinical placement. Objectives The objective of the study was to explore challenges experienced by nursing students during clinical placement with associated factors among highest institutions of Addis Ababa city, Ethiopia, 2020. Method A mixed method approach composed of cross sectional study and phenomenological method employed from February 15, to April 30, 2020 on 179 third- and fourth-year undergraduate nursing students selected using simple random sampling for the quantitative study and seven purposively selected students for qualitative study. Self-administered questionnaire and recording of telephone interview used to collect quantitative and qualitative data respectively. Logistic regression analysis carried out to identify the independent predictors, whereas the qualitative data analyzed using interpretation of the voice recorded during telephone interview, extracting significant statements, formulating meanings, and coding, categorizing into clusters of themes using the content analysis approach and using ATLAS ti.Version 7.5.16 software. Result the prevalence of challenge among nursing students was found to be 29 (16.9%).Consequently, in bivariate logistic regression, students’ religion, residence, entrance year, learning institution and substance use were found to have association with challenge among nursing student. However, in multivariable analysis only substance use and learning institution found to have significant association. Furthermore statistically significant negative moderate correlation between students total challenge score and their overall competency score were identified [r= -0.672, P value = < 0.001].In qualitative content regards student Nurses factors, lack of role model, instructors responsibilities, inadequate support structure & communication, lack of equipment and college responsibility were emerged. Conclusion It is essential to plan and improve students’ clinical supervision and support at clinical setting by their instructors and staff nurses to create skillful nursing students and minimize their challenge. Therefore there should be adequate orientation and ongoing follow-up for students before internship by principal instructors.

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