Records of past societies confronted with natural climate change can illuminate social responses to environmental stress and environment-disease connections, especially when locally constrained high–temporal resolution paleoclimate reconstructions are available. We present a temperature and precipitation reconstruction for ~200 BCE to ~600 CE, from a southern Italian marine sedimentary archive—the first high-resolution (~3 years) climate record from the heartland of the Roman Empire, stretching from the so-called Roman Climate Optimum to the Late Antique Little Ice Age. We document phases of instability and cooling from ~100 CE onward but more notably after ~130 CE. Pronounced cold phases between ~160 to 180 CE, ~245 to 275 CE, and after ~530 CE associate with pandemic disease, suggesting that climate stress interacted with social and biological variables. The importance of environment-disease dynamics in past civilizations underscores the need to incorporate health in risk assessments of climate change.