Psychological flexibility may reduce addictive behaviours by adaptive and flexible emotional and cognitive processes. This study tested a mediation model of internet gaming disorder (IGD) in which psychological flexibility would reduce depression and maladaptive cognitions related to internet gaming and in turn lower the risk of IGD. A cross-sectional study surveyed 2102 secondary 1–4 students from seven schools during March to November 2021 in Hong Kong, China. The results showed that 12.7% and 52.2% of the students were classified as having probable IGD and depression, respectively. The proposed mediation model fitted the data well: χ2/df = 8.00, CFI = .99, NNFI = .99, RMSEA = .01. Psychological inflexibility was directly and positively associated with IGD (B = .01, β = .07, p = .003) and indirectly and positively associated with IGD via depressive symptoms (B = .01, β = .07, p = .001, PM = 23.7%) and maladaptive cognitions (B = .03, β = .15, p = .001, PM = 50.8%). Multi-group analyses showed that gender significantly moderated the associations between psychological inflexibility and maladaptive cognitions (Δχ2/Δdf = 8.69/1, p < .05), between maladaptive cognitions and IGD (Δχ2/Δdf = 4.33/1, p < .05), and between psychological inflexibility and IGD (Δχ2/Δdf = 5.46/1, p < .05). Depression and maladaptive cognitions may be significant mediators that could explain the relationship between psychological flexibility and IGD. Also, gender difference may exist. Based on the findings, intervention strategies for IGD reduction are discussed.