The quantitative method and quasi-experimental design examined the effects of multimodal-multisensory instructional strategies (MMIS) on vocabulary acquisition and reading comprehension among students at-risk and students with disabilities in an inclusive environment. To discover the efficacy of multimodal-multisensory instructional strategies, numerical measures of central tendency were compared using t tests and fixed-effects model of analysis of variance. Similar analyses provided numerical information on the differences in groups based on the nominal variables of gender, ethnicity, and type of disability. This study compared the achievements of students who were instructed using MMIS and those taught by traditional techniques to determine if any significant differences in the achievement of students with disability and students at risk because of their participation in the MMIS study. The sample of this quasi-experimental study consisted high school students in a lower-socio-economic area in the southern part of the United States. The study observed the achievement scores of students from Biology and U.S. History courses. Two groups of students were instructed using MMIS and the other groups of students were taught using traditional methods. Student progress was measured using mixed ANOVA for repeated measures tests, and ANOVA for students in both the treatment groups and the comparison groups. Although students did make gains in their subject area, most of the results in the data analyses were not significant. However, there was significance found among students in Biology using the MMIS method of learning.