Across much of the eastern United States, oak forests are undergoing mesophication as shade-tolerant competitors become more abundant and suppress oak regeneration. Given the historical role of anthropogenic surface fires in promoting oak dominance, prescribed fire has become important in efforts to reverse mesophication and sustain oaks. In 2000 we established the Ohio Hills Fire and Fire Surrogate (FFS) study to examine whether repeated prescribed fire (Fire), mechanical partial harvest (Mech), and their combined application (Mech + Fire) reduced the dominance of subcanopy mesophytic competitors, increased the abundance of large oak-hickory advance regeneration, created a more diverse and productive ground-layer flora, and produced fuel beds more conducive to prescribed fire, reducing the risk of high-severity wildfire. Here we report on the ~20-year effects of treatments on vegetation and fuels and examine the support for interactive effects across a topographic-moisture and energy gradient. In general, we found that Fire and Mech + Fire treatments tended to reverse mesophication while the Mech-only treatment did not. The moderate and occasionally high-intensity fires resulted in effects that were ultimately very similar between the two fire treatments but were modulated by topography with increasing fire severity on drier sites. In particular, we found support for an interaction effect between treatment and topography on forest structure and tree regeneration responses. Fire generally reduced mesophytic tree density in the midstory and sapling strata across all site conditions, while leading to substantial gains in the abundance of large oak-hickory advance regeneration on dry and intermediate landscape positions. Fire also promoted ground-layer diversity and created compositionally distinct communities across all site conditions, primarily through the increased richness of native perennial herbs. However, the fire had limited effects on fine surface fuel loading and increased the loading of large woody fuels, potentially increasing the risk of high-severity wildfire during drought conditions. We conclude that two decades of repeated fires, with and without mechanical density reduction, significantly shifted the trajectory of mesophication across most of the landscape, particularly on dry and intermediate sites, highlighting the capacity of a periodic fire regime to sustain eastern oak forests and promote plant diversity but modulated by topography.