A new set of 17 unspiked K-Ar and five 40Ar/39Ar ages, together with previously published radiometric ages for the volcanic region around Lassen volcanic center (LVC) in the Southern Cascades, USA, shows that eruptive periods at LVC have occurred in close temporal relationship with mafic eruptive sequences within the broader Lassen region, up to 50 km from the LVC. The back-arc Caribou volcanic field (CVF, ~ 800–15 ka) and fore-arc volcanoes, active simultaneously with the LVC, are characterized by eruptive sequences that each persisted for 20–40 ky, with the most recent eruptions occurring during the last glacial episode (< 15 ky). Crater Mountain, a relatively young (282–395 ka) shield volcano spatially close to the CVF, confirms the presence of localized higher fluxes of mantle-derived melts that persisted for hundreds of thousands of years in the back-arc region. Crater Mountain eruptions overlap in time with LVC and CVF eruptions. Cumulatively, during the past 3.5 Ma, periods of intense regional mafic activity have occurred simultaneously with eruptive sequences at the silicic LVC. This link in eruption timing between the LVC and regional mafic volcanoes suggests that a broadly distributed increase in heat flux triggered spatially dispersed mantle-derived melt injections. The increase in regional melt injections triggered rejuvenation of crystal mushes beneath LVC, explaining the coincidence in eruption timing.