This study investigated Chemistry students' performance and retention (knowledge and understanding, knowledge and application, perception and attitude) in Organic Chemistry in three Senior High Schools (SHSs) within Tamale Metropolis in Ghana. Collaborative learning models were employed as intervention strategies. Quasi-experimental design was adopted for the study. The target population for the study was third year SHS Chemistry students. Two intact classes were used as control and experimental groups in each school. The research instruments were self-constructed Organic Chemistry Achievement Test (OCAT) and Students' Attitude and Perception Questionnaire (SAPQ). The Organic Chemistry Achievement Test data was analysed using t-test statistics whilst Students' Attitude and Perception Questionnaire data was analysed using descriptive statistics. The study revealed a 34.04% improvement in post-test mean scores on both knowledge and understanding, and knowledge and application due to the intervention. The study again revealed a significant improvement of (20%) in students' perceptions and attitudes towards Organic Chemistry due to the intervention. A statistically significant improvement of 25% in confidence level among students, towards Organic Chemistry, was recorded. Collaborative teaching and learning approaches were judged effective for ameliorating SHS learners, academic achievement and knowledge retention in Organic Chemistry concepts and were recommended for teaching and learning at SHS.