Background <p>Ultra-processed food (UPF) consumption has been steadily increasing globally, yet the associated risk of all-cause mortality remains unclear. We aimed to assess the risk of all-cause mortality of UPFs via an updated systematic review and dose-response meta-analysis.</p> Methods <p>A comprehensive literature search was conducted in PubMed, Embase, and Cochrane Library for studies published until July 2, 2024, in addition to referred studies included in the previous systematic review. Prospective cohort studies assessing the association between NOVA classification-defined UPF consumption and all-cause mortality were included. Dose-response meta-analysis via a random-effect model was used to combine the results with hazard ratio (HR) as an effect measure.</p> Results <p>Overall, 18 studies with 1,148,387 participants (173,107 deaths) were identified. Compared to the lowest, participants with the highest UPF consumption had a 15% increased risk of all-cause mortality (HR = 1.15, 95% CI 1.09–1.22; <i>I</i>² = 83.0%). Furthermore, a 10% higher risk of all-cause mortality was detected with each 10% increment in UPF consumption (HR = 1.10, 95% CI 1.04–1.16; <i>I</i>² = 91.0%). Dose-response analysis showed a positive linear association (<i>P</i>_{dose-response} &lt; 0.001). Moreover, subgroups and sensitivity analyses indicated consistent findings, while meta-regression analyses suggested sex distributions partially explained heterogeneity, with a higher risk of all-cause mortality in males.</p> Conclusions <p>Our updated meta-analysis, incorporating a greater number of newly published cohort studies using NOVA classification with the largest sample size to date, strengthens the evidence linking higher UPF consumption to increased all-cause mortality risk. Strategies such as dietary guidelines and policies for limiting UPF consumption worldwide should be encouraged.</p> Systematic review registration <p>PROSPERO CRD42023467226.</p>