Background: Childhood environmental unpredictability (CEU) is supposed to be associated with problematic smartphone use (PSU) in adulthood, but the evidence for the possible association paths to date is still insufficient. Objective: This study aimed to investigate the association between CEU and PSU in adulthood and the mediation roles of anxiety and self-control using a cross-sectional design. Methods: Totally 823 Chinese undergraduates (56.62% female; Mage = 20.66 years, SD = 1.53) completed a self-report questionnaire measuring CEU, self-control, anxiety, and PSU. A multiple mediation model was constructed to test the hypotheses using Mplus 7.4. Results: First, CEU was negatively associated with self-control (r = -.026, p < .001) and positively associated with anxiety (r = .27, p < .001) and PSU (r = .23, p < .001). Second, both parallel (anxiety, β = 0.04, SE = 0.01, 95% CI [0.02, 0.07]; self-control, β = 0.09, SE = 0.02, 95% CI [0.05, 0.13]) and sequential (β = 0.08, SE = 0.01, 95% CI [0.06, 0.10]) mediation analysis showed that anxiety and self-control mediated the relationship between CEU and PSU. Conclusions: The present study provides an understanding of how CEU influences PSU and highlights that reducing anxiety and improving self-control could be potential interventions to reduce the effects of CEU on PSU in college students.