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We performed a systematic review and dose–response meta-analysis of observational studies assessing the association between UPF consumption and adult mortality risk. A systematic search was conducted using ISI Web of Science, PubMed/MEDLINE, and Scopus electronic databases from inception to August 2021. Data were extracted from seven cohort studies (totaling 207,291 adults from four countries). Using a random-effects model, hazard ratios (HR) of pooled outcomes were estimated. Our results showed that UPF consumption was related to an enhanced risk of all-cause mortality (HR = 1.21; 95% CI: 1.13, 1.30; I² = 21.9%; <i>p</i> < 0.001), cardiovascular diseases (CVDs)-cause mortality (HR = 1.50; 95% CI: 1.37, 1.63; I² = 0.0%; <i>p</i> < 0.001), and heart-cause mortality (HR = 1.66; 95% CI: 1.50, 1.85; I² = 0.0%; <i>p</i> = 0.022), but not cancer-cause mortality. Furthermore, our findings revealed that each 10% increase in UPF consumption in daily calorie intake was associated with a 15% higher risk of all-cause mortality (OR = 1.15; 95% CI: 1.09, 1.21; I² = 0.0%; <i>p</i> < 0.001). The dose–response analysis revealed a positive linear association between UPF consumption and all-cause mortality (<i>P</i>_nonlinearity = 0.879, <i>P</i>_{dose–response} = <i>p</i> < 0.001), CVDs-cause mortality (<i>P</i>_nonlinearity = 0.868, <i>P</i>_{dose–response} = <i>p</i> < 0.001), and heart-cause mortality (<i>P</i>_nonlinearity = 0.774, <i>P</i>_{dose–response} = <i>p</i> < 0.001). It seems that higher consumption of UPF is significantly associated with an enhanced risk of adult mortality. Despite this, further experimental studies are necessary to draw a more definite conclusion.