The purpose of this study was to determine the effect of topic-specific pedagogical content knowledge-based instruction on grade 11 students' achievement in chemical kinetics and equilibrium. A quasi-experimental research design with a 4 × 2 * 3 pre-test and post-test control group was employed on Grade 11 chemistry students in Addis Ababa administrative city, Ethiopia. Each treatment was assigned to four schools at random. The data collection instrument was the chemistry achievement test and the instrument was piloted with 61 students in a different school than the intervention schools. The reliability coefficient of the chemistry achievement test was calculated to be 0.79 after piloting and using Kuder-Richardson Formula 20. Data was gathered and analyzed using descriptive statistics and analysis of variance. The study found that TSPCK-based instruction significantly improved high school students' achievement in chemical kinetics and equilibrium concepts. Students exposed to the conceptual teaching strategy instructional mode performed better academically than those in representation-based, curricular saliency-based and conventional groups. However, the interaction between the type of interaction with gender and achiever levels was insignificant. Female students in chemistry who were exposed to topic-specific PCK-based instructional modes showed greater mean and normalized learning gains than their male counterparts in all groups. This resulted in the female students, intervention groups, and achiever levels being enhanced by 19%, 21.3%, and 15% average normalized learning gains, respectively, in chemical kinetics and equilibrium. Therefore, it is recommended that teaching chemical kinetics and equilibrium using topic-specific PCK-based instructional modes is the preferred effective teaching strategy to enhance achievement of students.