Introduction: The relationship that socio-familial and non-cognitive variables have on students in regards to their academic performance is a very important element for success in Secondary Education. In this study the influence of non-cognitive variables (academic self-concept, self-efficacy and perceived family affective support) and socio-familial variables (educational level and expectations of each parent) on the academic performance of secondary school students were analysed. Method: Students were grouped according to their accumulated socio-familial risk index (at-risk students, n = 305; not-at-risk students, n = 991). To measure the variables, the scales What do you think of yourself, General Self-Efficacy and Perceived Family Support were used. Socio-family variables were measured with an ad hoc questionnaire, and academic performance with the end-of-course evaluation scores. Results: The receiver operating characteristic curve showed a decrease in students’ academic performance from three or more accumulated risks. Structural Equation Modelling (SEM) was performed for each group. The results showed that for at-risk students, academic performance was mainly determined by two variables: academic self-concept and self-concept; in contrast to the not-at-risk students in which self-efficacy was the one that had the greatest effect on performance. In both groups, the parents’ expectations were the family variable with the highest incidence being performance, although, for the at-risk group, the effect was greater. Conclusions: The relevance of the identification of non-cognitive and socio-familial variables on the academic performance of at-risk students in regards to secondary education due to socio-familial factors is discussed.