This study investigated the effect of an activity-based blended-hybrid learning model to address challenges of low academic performance and holistic development among senior secondary school students in Benue State, Nigeria, using a pre-test–post-test quasi-experimental control group research design. Two research questions and two hypotheses guided the study. The population comprised 8,673 SS2 Biology students in public senior secondary schools in Makurdi and Gboko Local Government Areas of Benue State. A sample of 162 students was selected using purposive and simple random sampling techniques, comprising an experimental group taught using the blended-hybrid learning model (n = 76) and a control group taught using the discussion method (n = 86). Data were collected using the Biology Academic Performance Test (BPT) and Holistic Development Rating Scale (HDRS), with reliability coefficients of 0.84 and 0.81, respectively. Research questions were answered using mean and standard deviation, while hypotheses were tested at 0.05 level of significance using Analysis of Covariance (ANCOVA). Findings revealed a statistically significant difference in academic performance between the groups, F (1, 159) = 149.388, p < .05, with a large effect size (0.484). A statistically significant difference was also found in holistic development, F (1, 159) = 35.966, p < .05, with a moderate effect size (0.184). It was concluded that the blended-hybrid learning model enhances students’ academic performance and holistic development in Biology. It was recommended that Biology teachers should adopt blended-hybrid learning model, while education stakeholders should provide adequate digital infrastructure and teacher training to support effective implementation.