This study aimed at exploring the instructional activities that could support students’ learning of science process skills by using chemistry-based computer simulations and animations. A total of 160 students were randomly selected and 20 teachers were purposively selected to participate in the study. Data were gathered in both qualitative and quantitative formats. This was accomplished through the use of a classroom observation checklist as well as a lesson reflection sheet. The qualitative data were analyzed thematically, while the quantitative data were analyzed using percentages. The key findings from the study indicated that chemistry-based computer simulations and animations through instructional activities, particularly formulating hypotheses, planning experiments, identifying variables, developing operational definitions and interpretations, and drawing conclusions, support students in learning science process skills. It was found that during the teaching and learning process, more than 70% of students were able to perform well in the aforementioned types of instructional activities, while 60% performed well in planning experiments. On the other hand, as compared to other instructional activities, planning experiments was least observed among students and teachers. Students can be engaged in knowledge construction while learning science process skills through the use of chemistry-based computer simulations and animations instructional activities. Therefore, the current study strongly recommends the use of chemistry-based computer simulations and animations by teachers to facilitate students’ learning of chemistry concepts in Tanzanian secondary schools.