In recent years, students' performance in Biology in the Senior Secondary Certificates Examination (SSCE) has not been encouraging. Studies have attributed fluctuating achievement of students in Biology to ineffective use of instructional strategies. If sustainable solution is not proffered to the issue of poor performance in Biology, it could hinder the fulfilment of educational goals for science, especially in the health sector. This study advocated the use of teaching strategies that will promote and encourage teachers to adopt learning strategies that will demand students to think critically and contribute effectively in class and the society at large. Therefore, this study was carried out to determined the effectiveness of guided and open inquiry instructional strategies on academic performance of secondary school students in Biology in Osun State. The non-equivalent pretest posttest quasi-experimental research design was used for the study. The population comprised all senior secondary school Biology students in Osun state. The sample consisted of Senior Secondary One (SS1) Biology students in their intact classes selected using multistage sampling procedure. Biology Achievement Test (BAT) was used to gather data for the study. Data collected were analysed using analysis of Covariance. From the study, the results showed that there was a significant difference between the experimental groups taught Biology using guided inquiry and open inquiry strategies, and the control group taught Biology using conventional method. Open inquiry strategy improve students' performance better than the other groups. Also, guided inquiry stimulate students' performance than conventional method. The study concluded that Open inquiry is a better teaching strategy; as it was more effective in improving the academic performance of students in Biology in the study area.