Background: While handgrip strength is associated with all-cause and cause-specific mortality, whether such associations are dose-dependent is largely unknown. Therefore, we conducted a systematic review on the dose-response relationship of handgrip strength with all-cause mortality, cancer, and cardiovascular mortality. Methods: The data source included three electronic databases (PubMed/MEDLINE, Web of Science and Scopus) from inception to 8 February 2022. Prospective cohort studies of healthy adults with objective measures of handgrip strength were included. Two researchers independently screened studies, extracted data, and assessed risk of bias. We used estimates regarding handgrip strength categories to conduct a random forest model, and a two-stage random-effects hierarchical meta-regression model pooling study-specific estimates for dose-response relationship. Outcomes included all-cause, cancer, and cardiovascular mortality. Reults: Forty-eight studies comprising 3,135,473 participants (49.6% women, age range 35–85 years) were included. Random forest models showed a significant inverse association between handgrip strength and all-cause and cause-specific mortality. Dose-response meta-analyses showed that higher levels of handgrip strength significantly reduced the risk of all-cause mortality within 26–50 kg (Higgin´s I2 =45.7%) in a close-to-linear inverse fashion. Cancer and cardiovascular mortality displayed a trend towards a U-shaped association with a significant risk reduction between 16 and 33 kg (Higgin´s I2 =77.4%), and a close-to-linear inverse shaped and significant risk reduction ranging from 24 to 40 kg (Higgin´s I2 =79.7%) respectively. Conclusion: There is strong evidence for an association between lower handgrip strength with higher all-cause, cancer, and cardiovascular mortality risk. The dose-response relationship of handgrip strength substantially varies depending on the cause of mortality.