The study sought to investigate the effect of computer simulation and computerised molecular modeling software on teaching and learning of hybridisation in senior high schools. The framework for the study was hinged on constructivists and conceptual change theories. A quasi-experimental design, which made use of non-equivalent comparison group design, was used on science students at Odorgonno Senior High School in Ga Central District of Greater Accra Region of Ghana. A pre-test was used to categorise 129 students into a control group and experimental groups (intact class, individual and cooperative learning groups). The control group was taught using the traditional approach whilst the experimental groups were treated using computer simulation and computerised molecular modeling software for two weeks. Afterwards, post-test was administered to the groups in order to identify differences in their academic achievements. Statistical analysis of the pre and post-tests scores showed more improvement in the performance of the experimental groups than the control group. An independent sample t-test results showed a statistical significant difference between the performance of students in the experimental group (intact class group) and the control group (p =7.77x10-12 , p < 0.05) after treatment. The study revealed that computer simulation and computerised molecular modeling software had positive effect on the teaching and learning of hybridisation. Also, student's performance in the cooperative group setting was better than the individualised learning environment. It is recommended that chemistry teachers should adopt computer simulation and computerised modeling software in teaching and learning hybridisation in Senior High Schools in a cooperative learning environment.