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This study investigated the effects of differentiated and blended instructional strategies on students' interest and achievement in chemical combination in Bwari Area Council, Abuja, Nigeria. Two research questions were raised, and two null hypotheses were formulated and tested at the 0.05 level of significance. A quasi-experimental design with a pretest, posttest, and a control group was adopted. The population comprised 1,290 Senior Secondary One (SS1) chemistry students in public secondary schools in Bwari, Federal Capital Territory, Abuja. A sample of 158 students was selected using simple random sampling. Three intact classes from three schools were used, with two assigned to experimental groups and one to a control group. Two instruments were used for data collection: the Chemical Combination Interest Rating Scale (CCIRS) and the Chemical Combination Achievement Test (CCAT). Experts validated the instruments. Reliability coefficients of 0.84 for CCAT using Kuder-Richardson 21 and 0.81 for CCIRS using Cronbach's Alpha were obtained. Data were analyzed using means and standard deviations, and ANCOVA was used to test hypotheses at the 0.05 significance level. Bonferroni post hoc analysis determined the direction of differences. Findings revealed that students taught using differentiated and blended instructional strategies had significantly higher interest and academic achievement in chemical combination than those taught using the conventional method. The study concludes that both instructional strategies are effective in improving students' interest and achievement in chemical combination. It is recommended that chemistry teachers adopt differentiated instruction to address learners' diverse needs and integrate blended learning approaches to enhance active participation and understanding of abstract chemistry concepts.