Computer-assisted instruction (CAI) for students with disabilities can be categorized into the following categories: visual, auditory, mobile, and cognitive skills-based CAI. Cognitive-skills based CAI differs from other types of CAI largely in terms of an emphasis on instructional design features. We conducted both systematic review of literatures and meta-analysis of studies using cognitive skills-based CAI to determine the effectiveness of this technology on the learning outcomes of students with disabilities. This study also scrutinized critical instructional design features of CAI used in the synthesized studies. Results indicated (a) a moderate weighted average effect size of 0.35 for group-comparison design studies; (b) relatively large effect sizes, but inconsistent among different indices, in single-subject experimental design studies; and (c) insufficient information available on design features of the CAI used in the primary studies. Limitations, implications, and future research directions were discussed.