Recent years have seen a considerable growth of interest in the study of life stress and non-suicidal self-injury (NSSI). The current article presents a systematic review of the empirical literature on this association. In addition to providing a comprehensive meta-analysis, the current article includes a qualitative review of the findings for which there were too few cases (i.e., < 3) for reliable approximations of effect sizes. Across the studies included in the meta-analysis, a significant but modest relation between life stress and NSSI was found (pooled OR = 1.81 [95% CI = 1.49–2.21]). After an adjustment was made for publication bias, the estimated effect size was smaller but still significant (pooled OR = 1.33 [95% CI = 1.08–1.63]). This relation was moderated by sample type, NSSI measure type, and length of period covered by the NSSI measure. The empirical literature is characterized by several methodological limitations, particularly the frequent use of cross-sectional analyses involving temporal overlap between assessments of life stress and NSSI, leaving unclear the precise nature of the relation between these two phenomena (e.g., whether life stress may be a cause, concomitant, or consequence of NSSI). Theoretically informed research utilizing multi-wave designs, assessing life stress and NSSI over relatively brief intervals, and featuring interview-based assessments of these constructs holds promise for advancing our understanding of their relation. The current review concludes with a theoretical elaboration of the association between NSSI and life stress, with the aim of providing a conceptual framework to guide future study in this area.