Internet gaming disorder (IGD) is an emerging behavioral addiction with mental health implications among adolescents. Low self-control is an established risk factor of IGD. Few studies have, however, examined the moderating role of meaning in life (MIL) on the relationships between low self-control and IGD symptoms and functioning. This study aimed to examine the effects of low self-control and MIL and their interaction effects on IGD symptoms and family and school functioning in a structural equation model. A sample of 2064 adolescents (967, 46.9% male; mean age 14.6 years) was recruited by multistage cluster random sampling from 5 middle schools in Sichuan, China, in 2022. The participants completed a self-report questionnaire with validated measures on low self-control, presence of MIL, search for MIL, IGD symptoms, school commitment, and family functioning. Construct validity, measurement invariance, and structural invariance of the measures were evaluated by confirmatory factor analysis across sex. Structural equation modeling was conducted to examine the indirect effects of low self-control and MIL on family and school functioning through IGD symptoms. Latent moderated structural equation modeling was performed to examine the interaction effects between low self-control and MIL on IGD symptoms, school commitment, and family functioning. All scales showed satisfactory model fit and scalar measurement invariance by sex. Males showed significantly greater IGD symptoms and lower levels of self-control (Cohen d=0.25-1.20, P<.001) than females. IGD symptoms were significantly and positively associated with impulsivity (β=.20, P=.01), temper (β=.25, P<.001), and search for meaning (β=.11, P=.048) and significantly and negatively associated with presence of meaning (β=-.21, P<.001). Presence of MIL and impulsivity showed a significant and negative interaction effect (β=-.11, SE .05; P=.03) on IGD symptoms. The positive effect of impulsivity on IGD symptoms was stronger among adolescents with low presence of MIL than those with high presence of MIL. Temper showed significant and positive interaction effects with presence of MIL (β=.08, SE .04; P=.03) and search for MIL (β=.08, SE .04; P=.04) on family functioning. The negative effects of temper on family functioning were stronger among adolescents with low levels of MIL than among those with high levels of MIL. This study provides the first findings on the interaction effects between low self-control and presence of MIL and search for MIL on IGD symptoms and functioning among a large sample of adolescents in rural China. The results have implications for targeted interventions to help male adolescents with lower self-control and presence of meaning.