The purpose of this research was the effect of information and communication technology (ICT) skills on entrepreneurship, self-efficacy and academic performance in students. The research type was descriptive correlative, and with respect to purpose, it was applied. The statistical population consisted of all the 9353 students in Universities of Kashan and Medical Sciences in academic year 2014-2015, among whom, using Cochran Formula, 239 persons were chosen through stratified randomized sampling. The information gathering tools were ICT questionnaire with 25 items, entrepreneurship questionnaire with 20 items, self-efficacy questionnaire with 20 closed-ended questions and academic performance (GPA). To measure the validity of the questionnaires, content and construction validity (confirmative factor analysis) were used. Using Cronbach Alpha, the reliability coefficients were obtained equal to 0.84 for ICT, 0.79 for entrepreneurship and 0.81 for self-efficacy. For data analysis in inferential level, one sample t-test, Pearson correlation coefficient, regression and structural equation modeling through SPSS and Amos softwares were used. Findings showed that the mean of ICT skills was bigger than average and the means of entrepreneurship and self-efficacy were lower than average. There was a positive and significant relationship between ICT skills and entrepreneurship and self-efficacy. Also, there was a positive and significant relationship between ICT skills in training component and academic performance. However, there was a negative and significant relationship between ICT skills in research component and academic performance.