Teaching strategies play a vital role in improving learners' performance. This study investigated the effect of Guided Discovery Instructional Strategy (GDIS) on Grade nine learners' performance in chemical reactions and determined the effect of GDIS on gender. A quasi-experimental design with a sample comprising 75 grade nine learners was purposively selected from two schools in Mankweng Circuit based on Grade 12 performance. Learners were randomly assigned to the Experimental Group (EG) (N = 40) and Control Group (CG) (N = 35) taught for two weeks using GDIS for EG and Talk and Chalk Method (TCM) for CG. The results show that there were statistically significant differences in post-test of EG (M = 67.60, SD = 18.70) and CG (M = 37.86, SD = 18.01) (T-test: t(73) = 6.99; p < 0.05) and a Cohen d = 0.6. EG taught using GDIS outperformed CG taught using TCM (ANCOVA: F = 15.93, p < 0.05). GDIS favoured both males and females (Mann Whitney U-test: U = 153.00, p = 0.22, suggesting that GDIS improved all learners' performance in chemistry, but not TCM. The findings provide teachers and stakeholders with empirical evidence on a strategy that improved learners' performance. Also, GDIS did not discriminate against gender, suggesting that the strategy encourages girls to study science, contributing to narrowing the existing gender gap between males and females in Science, Technology, Engineering and Mathematics (STEM) subjects.