The research was on the effect of practical-based instruction on senior secondary students’ achievement and retention in genetics in Ekiti, Nigeria. The moderating effect of gender was also examined. The study adopted the pretest, posttest, control group, quasi-experimental research design. The instrument used for data collection was Genetics Achievement Test (GAT) with the reliability value of 0.82 using Pearson Product Moment Coefficient. The target population of this study was 1356 which was the population of SSII Biology students in the study area. A sample of 292 students comprising 158 boys and 134 girls drawn from 6 schools in the Local government area selected using multi-stage sampling Procedures. Three research questions and four null hypotheses guided the study. The hypotheses were tested at 0.05 level of significance using Analysis of Covariance (ANCOVA). The study revealed that students taught genetics using practical-based instruction had significantly higher mean achievement scores and retention than those taught using conventional method F=555.374, P(0.0001