This study aimed at investigating the effects of deploying mastery and active learning strategies in teaching difficult concepts and student's achievement and retention in Senior Secondary School Chemistry. A total of 235 Senior Secondary School Two chemistry students will be involved in the study. This number was made up of 123 males and 112 females drawn from ten secondary schools in Calabar Education Zone of Cross River State. Three research questions and three research hypotheses were formulated to guide the study and were tested at 0.05 level of significance. Quasi experimental design was used for the study, adopting a non-randomized pretest-posttest control group with 3x3x2 factorial arrangement. Three research instruments were used to gather data for the study namely Chemistry Achievement Test (CAT), Chemistry Retention Test (CRT) and Cognitive Ability Test (CAT). Also, Kuder-Richardson formula-21 was used to establish the reliability of Chemistry Achievement Test (CAT). Data collected was analyzed using Analysis of Covariance (ANCOVA) and Scheffe Post Hoc analysis was used to obtain the direction of significance. Based on the result of the findings indicating the efficacy pf mastery and active learning strategies, it was concluded that Mastery learning strategy facilitate students performance and retention in the concept of quantum number follow by active learning strategy. It was therefore recommended that science teachers should adopt Mastery and Active learning strategies to teach various concepts in chemistry.