The Italian peninsula offers an excellent case study within which to investigate long-term regional demographic trends and their response to climate fluctuations, especially given its diverse landscapes, latitudinal range and varied elevations. In the past two decades, summed probability distributions of calibrated radiocarbon dates have become an important method for inferring population dynamics in prehistory. Recent advances in this approach also allow for statistical assessment of spatio-temporal patterning in demographic trends. In this paper we reconstruct population change for the whole Italian peninsula from the Late Mesolithic to the Early Iron Age (10,000–2800 cal yr BP). How did population patterns vary across time and space? Were fluctuations in human population related to climate change? In order to answer these questions, we have collated a large list of published radiocarbon dates (n = 4010) and use this list firstly to infer the demographic trends for the Italian peninsula as a whole, before addressing each of five sub-regions in turn (northern, central, and southern Italy, Sicily, Sardinia). We also compare population fluctuations with local paleoclimate proxies (cave, lake, marine records). At a pan-regional scale, the results show a general rapid and substantial increase in population in the Early Neolithic with the introduction of farming at around 8000 cal yr BP and further dramatic increases during the Bronze and Iron Age (~ 3800–2800 cal yr BP). However, different regional demographic trajectories exist across different regions of Italy, suggesting a variety of localised human responses to climate shifts. Population and climate appear to have been more closely correlated during the early–mid Holocene (Mesolithic–Neolithic), while later in the Holocene (Bronze–Iron Ages) they decouple. Overall, across the Holocene the population dynamics varied by region and depended on the long-term socio-ecological dynamics prevailing in a given area. Finally, we include a brief response to the paper ‘Radiocarbon dated trends and central Mediterranean prehistory’ by Parkinson et al. (J Word Prehist 34(3), 2021)—synchronously published by Journal of World Prehistory but wholly independently developed—indicating how our conclusions accord with or differ from one another.