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The study examined the impact of differentiated instruction on chemistry students, interest and motivation, as well as their achievement and how they retained what is learned when taught chemistry using differentiated instruction. Today, all over the world, researchers have suggested several approaches to teaching aimed at enhancing learning and retention of what has been learned. This study therefore compared the use of differentiated approach to learning chemistry with the one-site fit-all approach. The population of the study consisted of 604 senior secondary II students in Bwari Area Council of the Federal Capital Territory (FCT). The study adopted a non-randomized, quasi-experimental design, with an intact class of 604 students forming the sample of the study. Three instruments—CSIIQ, SAT, and STMLCQ—were used to gather data from the respondents. The instruments were pilot tested, and their reliability was computed using Kuder-Richardson (KR-21) yielding a coefficient of 0.78, 0.72, and 0.86, respectively. The collected data was used to answered the research questions and test the hypotheses stated. Research questions were answered using mean and standard deviation score while Analysis of Covariance (ANCOVA) was used to test the hypotheses. The result of the study revealed that the differentiated approach significantly affects students’ interest (F =116, p = 0.001< 0.05) and motivation (F = 126.243, p = 0.002< 0.050) to learn chemistry as compared to the one-site fit-all approach. It was also revealed that students exposed to differentiated learning approaches achieved significantly higher mean scores (F = 146.112, p = 0.001<0.050) and higher retention mean scores (F = 136.162, p = 0.003<0.05). It was recommended that chemistry teachers adopt differentiated approach to teaching and learning to draw students’ interest in chemistry. The study concluded that, in addition to reducing students’ attrition in chemistry, differentiated instruction is key to motivating students toward learning chemistry.