Drug abuse has been and continues to be, a common social issue worldwide, yet the efficiency of widely adopted sweeping speech for anti-drug campaigns has proven inefficient. To provide students with a safe and efficient learning situation related to drug refusal skills, we used a novel approach rooted in a serious learning game and concept map during a brief extracurricular period to help students understand drugs and their negative effects. The proposed game-based situational learning system allowed all students to participate simultaneously and individually in multiple scenarios of drug temptation posed by peers and classmates to practice responding and refusing drugs in school and community settings. Moreover, to explore whether different personality traits (such as the Big Five personality traits) result in different anti-drug responses, we used a serious game to conduct an anti-drug experiment on 53 junior middle school students aged 13 to 15. Each participant’s decision-making process was recorded in the serious game as behavioral patterns for lag sequential analysis (LSA). The outcomes revealed seven behavioral patterns including differentiation (D), acceptance (A), effective (ER) and ineffective responses (IR), effective (ES) and ineffective solution-seeking (IS), and failure to refuse (F). The GSEQ (Generalized Sequential Querier) which is a computer program for analyzing sequential observational data was used. The results indicated the following: (1) Neuroticism was performed at a relatively low level under the guidance of a concept map. (2) “Neuroticism” was associated with the lowest risk of accepting drugs. (3) Students with “openness to experiences” were at high risk of accepting drugs. (4) Almost all personality behavioral transition diagrams showed that failure to refuse (F) drugs was followed by inefficient seeking of help (SI) and inefficient refusal (RI). These findings provide reference points for designing adaptive anti-drug education programs.