© 2022 The Author(s)Background: The non-causal and causal associations, possible age and sex differences between living alone and all-cause mortality among adults were unclear. We aimed to assess the association and causal relation between living alone and all-cause mortality among community-dwelling adults, addressing the certainty of evidence, possible age and sex differences. Methods: We searched Medline, Embase, and APA PsycINFO for cohort studies examining the association between living alone and all-cause mortality on November 19, 2021. We used the GRADE approach to assess certainty of evidence, and the Instrument for the Credibility of Effect Modification Analyses (ICEMAN) to evaluate credibility of subgroup inferences and conducted a meta-analysis of measures of association between living alone and mortality. The study was registered with PROSPERO, CRD42021290895. Findings: 18 cohort studies with 62,174 adults proved eligible. Living alone was associated with mortality (relative risk (RR) = 1.15, 95% confidence interval (CI) 1.08–1.23). Both age and sex modified the association (high and moderate credibility, separately). Living alone increased the risk of dying only in younger but not older individuals (ratio of RRs = 1.59, interaction P = 0.003; younger RR 1.41, 95% CI 1.17–1.71, high certainty for prognosis, low for causation; older RR = 1.05, 95% CI 0.91–1.22, moderate certainty for prognosis, very low for causation). Living alone increased risk to a greater extent in males than females (ratio of RRs = 1.39, 95% CI 1.14–1.70; interaction P = 0.001, males RR = 1.41, 95% CI 1.17–1.71, high certainty for prognosis, low for causation; females RR = 1.15, 95% CI 0.99–1.33; moderate for prognosis factor, very low for causation). Interpretation: Living alone is associated with increased mortality in individuals under 65 years (high certainty) but not with those over 75 years; the association may be causal (low certainty). Associations, and possibly effects, may be stronger in men than women. Funding: None.