Engaging students in the essential practices of science has been forwarded as an effective means to achieve scientific literacy for all students by promoting the learning of content, procedures, and the epistemology of science concurrently. However, the emphasis on science practices requires teachers not only to develop skills and knowledge specific to the science practices, but also to adopt epistemic orientations congruent with student-centered, knowledge generation science teaching approaches. This exploratory quantitative study examined the relationships between secondary science teachers' epistemic orientations and their understanding and self-reported implementation of the science practices described in the US Next Generation Science Standards (NGSS). This study also identified teacher-level variables that predict teachers' epistemic orientations, their understanding and implementation of the science practices. Data were collected from 128 secondary science teachers in a southeastern state of the US using three instruments: epistemic orientation survey with demographic questions, epistemic nature of science practice survey, and science practice implementation survey. One-way analysis of variance, correlation analyses, multiple linear regression, and path analyses were used to examine the relationship among these three variables and the influence of teacher-level variables on each of the three variables. Our results indicated that teachers' participation in NGSS PD programs significantly predicted their self-reported implementation of science practices. In addition, teachers' lateral entry was the only significant predictor of teachers' epistemic understanding of science practices. Concerning the relationship among the three variables, the path analysis revealed that teachers' epistemic orientations significantly mediated the relationship between their epistemic understanding and implementation of science practices (x[superscript 2]/df = 1.530, p = 0.216, comparative fit index = 0.980, Tucker-Lewis index = 0.940, root-mean-square error of approximation = 0.065). This study highlights a close relationship between teachers' epistemic orientations and enactment of science practices, which suggests prioritizing epistemic orientations in supporting teachers to implement the science-as-practice approach.