A teacher’s orientation, self-efficacy, and instructional practices can affect student learning outcomes, especially in reading comprehension. This sequential explanatory strategy mixed-method study sought to gain insight into reading comprehension instruction by integrating quantitative (Phase I) and qualitative (Phase II) findings. The researcher examined the effects of teachers’ orientation to literacy instruction and self-efficacy toward culturally responsive pedagogy and the effect on student reading comprehension and alignment to their reading comprehension instructional practices in racially, ethnically, and/or linguistically diverse fourth- and fifth-grade classrooms. The first integrated analysis revealed that most teachers’ aligned with an Eclectic orientation; the Constructivist oriented teachers’ students made a significantly higher gain in reading comprehension than the students whose teachers held a Traditional orientation. Phase II teachers’ LOS orientation aligned with their interview responses and observed instructional practices. The second integrated analysis revealed that most Phase I teachers were rated as having moderate or high self-efficacy; teachers’ level of self-efficacy toward culturally responsive pedagogy had no statistically significant effect on students’ reading comprehension achievement; and Phase II teachers rarely or occasionally incorporated culturally responsive pedagogical practices during their observed lessons. These findings support that the relationship between teachers’ level of self-efficacy toward culturally responsive pedagogy and their effect on student reading comprehension and alignment to their reading comprehension instructional practices is not as straightforward as prior research may have assumed.