Background: For 60 y, the people of Asubpeeschoseewagong Anishinabek (Grassy Narrows First Nation) have endured the effects of massive mercury (Hg) contamination of their river system, central to their traditions, culture, livelihood, and diet. In the years following the Hg discharge into the English-Wabigoon River system by a chloralkali plant in the early 1970s, there was a dramatic increase in youth suicides. Several authors attributed this increase solely to social disruption caused by the disaster. Objective: This research examined the possible contribution of Hg exposure across three generations on attempted suicides among today's children (5-11 y old) and youth (12-17 y old), using a matrilineal intergenerational paradigm. Methods: Information from the 2016-2017 Grassy Narrows Community Health Assessment (GN-CHA) survey was merged with Hg biomonitoring data from government surveillance programs (1970-1997). Data from 162 children/youth (5-17 years of age), whose mothers (n = 80) had provided information on themselves, their parents, and children, were retained for analyses. Direct and indirect indicators of Hg exposure included a) grandfather had worked as a fishing guide, and b) mother's measured and estimated umbilical cord blood and childhood hair Hg and her fish consumption during pregnancy with this child. Structural equation modeling (SEM) was used to examine significant links from grandparents (G0) to mothers' exposure and mental health (G1) and children/youth (G2) risk for attempted suicide. Results: Mothers' (G1) median age was 33 y, 86.3% of grandmothers (G0) had lived in Grassy Narrows territory during their pregnancy, and 52.5% of grandfathers (G0) had worked as fishing guides. Sixty percent of children (G2) were Discussion: Despite minimal individual information on G0 and G1 past life experiences, the findings support the hypothesis that Hg exposure over three generations contributes to the mental health of today's children and youth. The prevalence of Grassy Narrows youth ever having attempted suicide is three times that of other First Nations in Canada. https://doi.org/10.1289/EHP11301, Introduction Since the first public evidence, 52 y ago, of the extent of the mercury (Hg) discharge into the English-Wabigoon River system by a chloralkali plant in Dryden, Ontario (Canada), [...]