The study investigated the effect of hands-on activity-based method on interest of senior secondary chemistry students in organic chemistry. The study adopted a quasi-experimental design. A sample of 184 students from four purposively selected secondary schools out of a population of 2,381 SS II students from Makurdi Local Government Area of Benue State, Nigeria was used for the study. The experimental group was taught organic chemistry using hands-on activity-based method while the control group was taught using discussion method. Two research questions and two hypotheses guided the study. A validated 25-item Organic Chemistry Interest Inventory (OCII) was the instrument used to collect data. Reliability coefficients of 0.84 were established using Cronbach Alpha. Mean and Standard Deviation scores were used to answer the research questions while Analysis of Covariance (ANCOVA) was used to test the hypotheses at 0.05 level of significance. The results indicated that students taught using hands-on activity-based had significantly higher mean interest scores than those taught using discussion method (F=387.370, P(0.0001<0.05). Male and female students in hands-on activity-based group did not differ significantly in mean interest scores (F= 117.523, P(0.101>0.05). It was recommended that teachers should be encouraged to adopt hands-on activity-based method in teaching organic chemistry to enhance students’ interest in organic chemistry.