Deaths of despair, morbidity and emotional distress continue to rise in the US. The increases are largely borne by those without a four-year college degree—the majority of American adults. For many less-educated Americans, the economy and society are no longer providing the basis for a good life. Concurrently, all-cause mortality in the US is diverging by education—falling for the college-educated and rising for those without a degree—something not seen in other rich countries. We review the rising prevalence of pain, despair, and suicide among Americans without a BA. Pain and despair created a baseline demand for opioids, but the escalation of addiction came from pharma and its political enablers. We examine “the politics of despair,” how less-educated people have abandoned and been abandoned by the Democratic Party. While healthier states once voted Republican in presidential elections, now the least-healthy states do. We review the evidence on whether or not deaths of despair have risen during the COVID pandemic. More broadly, excess mortality from COVID has not increased the ratio of all-cause mortality rates for those without and with a four-year degree, but has instead replicated the pre-existing mortality ratio.