Students with significant intellectual and developmental disabilities deserve access to instruction on academic skills in addition to functional skills. Many teachers, however, report challenges with identifying appropriate evidence-based practices to teach academics to these students. The purpose of this systematic review was to summarize and analyze literature on academic instruction for students with significant disabilities. Two hundred twenty-two articles with 225 experiments utilizing a single-case design and published between 1976 and 2018 were included in the review. Visual analysis indicated that, in most cases, interventions enabled students to make progress on targeted academic skills. The majority of studies focused on basic reading skills and included participants with moderate disabilities. Most studies used a combination of three or four evidence-based practices, with modeling, prompting, visual supports, time delay, and reinforcement being the most frequently used combination across studies.