Students with mild intellectual disabilities need explicit vocabulary instruction with multiple exposures in different contexts and extra practice in associating meanings to unfamiliar words to build their word knowledge. The purpose of this study was to examine the effect of multimedia-based computer assisted instruction on learning the meanings of words compared to the identical instruction without computers. Forty, Year 7 to 10 students were explicitly taught vocabulary words either via computer-assisted or teacher-directed instruction. The story "Charlotte's Web" was used as a context through a variety of evidenced-based instructional practices. The students' pre and post tests were based on Read's Word Associates Format (WAF) vocabulary test. Both the groups significantly improved their scores on post tests and retained most of the new learning five-months later suggesting that a multimedia programme could be used to improve vocabulary knowledge as effectively as a teacher. However, when comparing instructional tasks using Stahl's Depth of Processing model, there were differences that imply some instructional methods were more suited for multimedia presentation. This has implications for teacher practice regarding when to use computer-assisted instruction with students who have a mild intellectual disability.