Objectives. To evaluate changes in mortality in US counties along the US-Mexico border in which there was substantial new border wall construction after the Secure Fence Act of 2006 relative to border counties in which there was no such border wall construction. Methods. Using complete 1990 to 2017 mortality microdata and a quasi-experimental difference-in-differences design, we evaluated changes in overall (all-cause) mortality, mortality from drug overdose, and mortality from homicide in the 10 counties with substantial new border wall construction and 11 counties with no such construction. We fit a linear model, adjusting for population characteristics and county and year fixed effects, with Bonferroni adjustments for multiple comparisons. Sensitivity analyses included the addition of adjacent inland counties and modifications to the statistical model. Results. Relative to counties without substantial new border wall construction, counties in which a substantial amount of new border wall was constructed exhibited a nonsignificant 0.02-percentage-point increase (95% confidence interval [CI] = -0.06, 0.10; P > .99) in overall mortality after construction. Border wall construction was not associated with changes in either deaths from overdose or deaths from homicide. Conclusions. Wall construction along the US-Mexico border after the Secure Fence Act of 2006 was not associated with discernible changes in mortality.