This study examined the role of science domain knowledge, reading motivation, and decoding skills in reading comprehension achievement in third-grade students who are English learners (ELs) and students who are monolingual, using a nationally representative data set. Multigroup probit regression analyses showed that third-grade science domain knowledge and motivation for reading, decoding skills, and early attainment of decoding skills were significantly associated with third-grade reading comprehension in both language groups. Also, using Wald chi-square tests, the study showed that the association between third-grade science domain knowledge and reading comprehension was stronger in students who were ELs than in students who were monolingual. These findings suggest that cultivating science domain knowledge is very important to supporting reading comprehension development in third grade, particularly for students who are ELs.