This study investigated the effects of three strategies (i.e., guided discovery, think-pair-share, and lecture) on senior secondary school students’ achievement in chemistry. A pretest, posttest, control group quasi-experimental design with a 3 × 3 × 2 factorial matrix was adopted for the study. Treatment was at three levels (guided discovery, think-pair-share, and lecture strategies). Intervening variables were cognitive entry behavior at three levels (high, middle, and low) and gender at two levels (male and female). Two hundred forty-two Senior Secondary 1 students in intact classes from six secondary schools in Ijebu Ode and Odogbolu Local Government Areas of Ogun State were randomly assigned to the treatment and control groups. Three instruments were developed and used to collect data from students during the 8-week treatment program. The data collected were subjected to analysis of covariance and multiple classification analysis. Scheffé test was further used as post hoc measures. Where significant interactions were observed, they were represented with graphical illustrations. It was found that students taught with guided discovery and think-pair-share strategies obtained significantly higher posttest mean scores than those in the lecture strategy, F(4, 223) = 51.66, p < .05. The use of guided discovery and think-pair-share strategies had great potential for improving achievement in chemistry and science learning generally.