With a focus on content-area reading, this study aimed to (a) understand the sources and prevalence of concurrent and specific difficulties in word-level skills, vocabulary, and knowledge among adolescent struggling readers (ASRs) and (b) explore the relations among reading skills, profiles, and reading comprehension. A dual-measure screening approach was used to classify a sample of 492 seventh- and eighth-graders. Among the subgroup of 225 ASRs, five distinct profiles were identified by latent profile analysis. The results confirmed the following: (a) the heterogeneity of reading difficulties in adolescents; (b) the universal prevalence of vocabulary difficulties across various language systems; and (c) the finding that fluency, rather than word accuracy, presents a more significant challenge at the word level in ASRs. Additionally, academic vocabulary knowledge and content-area knowledge independently predict content-area reading comprehension, even after accounting for general reading comprehension. This implies that preventive and remedial efforts for adolescent reading difficulties should prioritize and tailor crucial components of content-area reading.