Situated in the context of an in-service professional development (PD) program focused on Interdisciplinary Science Inquiry, this quantitative study tests the validity of and further explores the theoretical model adapted from Desimone's (2009), "Educational Researcher," 38, 181-199 conceptual framework on effectiveness of PD. The participants include 204 teachers and 5,581 students within 12 local public schools from 2012 to 2016. The multilevel models indicate that PD participation, school-, and teacher-level factors influence teacher pedagogical content knowledge and inquiry instruction in different ways. Furthermore, the inquiry instruction significantly relates student understanding of interdisciplinary science concepts (ISCs) through a few mediators. Therefore, this study reinforces calls to provide teachers with high quality PD and contributes to current knowledge base of the mechanisms of how inquiry instruction influences students' understanding of ISCs.