Approaches to teaching science are undergoing a mutation and new variants such as the Culturo-Techno-Contextual Approach (CTCA) have emerged and are proving to be more potent than the older variants. This study explored the efficacy of CTCA in reducing learning anxiety and promoting meaningful learning of chemistry among secondary school students by comparing the performance of the two experimental groups with that of the control group. The study employed an explanatory sequential design. The quantitative phase was quasi-experimental, while the qualitative phase was an in-depth interview. A total of 141 senior secondary II students (the equivalent of grade 11) from three purposively selected schools in Lagos State education district V were sampled. The Electrochemistry Achievement Test and revised Science Anxiety Scale which had reliability coefficients of 0.78 and 0.95, respectively, were the instruments used to collect quantitative data, while the students’ perception about CTCA interview guide was used to collect the qualitative data. The two experimental groups were taught using CTCA in a face-to-face class and blended learning mode, while the control group was taught using the traditional lecture method. Treatment lasted five weeks after which posttest and retention test (four weeks after posttest) were conducted. Quantitative data were analyzed using one-way MANCOVA, the qualitative data were analyzed using framework analysis. The results showed that each of the CTCA groups outperformed the lecture group on measures of achievement (F(2,136) = 72.05; p < 0.01) and anxiety (F(2,136) = 11.87; p < 0.01). CTCA was also found not to have a significant differential impact on the experimental groups based on gender. By these results, it was inferred that irrespective of the learning platforms (online or physical), CTCA has the potency to improve students’ understanding of chemistry concepts compared to the traditional lecture method. Therefore, within the limitations of the study, it was concluded that CTCA is a viable teaching approach for reducing learning anxiety and promoting meaningful learning of chemistry concepts. Open doors for future exploration were also highlighted.