The southern Tibetan Plateau margin between ~ 83°E and 86.5°E is defined by an abrupt change from the low-relief Tibetan Plateau to the rugged topography and deep gorges of the Himalaya. This physiographic transition lies well to the north of active thrusting, and thus, the mechanism responsible for the distinct topographic break remains the focus of much debate. While numerous studies have utilized thermochronology to examine the exhumation history of the Himalaya, few have done so with respect to variations across the Himalaya-Tibetan Plateau transition. In this work, we examine the nature of the transition where it is accessible and well-defined in the Nyalam valley of south-central Tibet. We employ several new and previously published thermochronologic datasets (with a closure temperature range of ~ 70°C–300°C) in conjunction with river incision patterns inferred by the longitudinal profile of the Bhote Kosi River. The results reveal a sharp change in cooling rate at ~ 3.5 Ma at a location corresponding to a pronounced river knickpoint representing a sharp increase in river gradient and presumably incision rate (a proxy for rock uplift). Margin retreat models for the physiographic transition are inconsistent with the cooling pattern revealed by low-temperature thermochronologic data. Models invoking passive uplift of the upper crust over a midcrustal ramp and associated duplex to account for the physiographic transition do not explain the observed break in cooling rate there, although they may explain a suggesting in the thermochronologic data of progressively increasing exhumation rates south of the transition. The simplest model consistent with all observations is that passive uplift is augmented by contemporaneous differential uplift across a young (Pliocene-Quaternary) normal fault at the physiographic transition. Drawing on observations elsewhere, we hypothesize that similar structural relationships may be characteristic of the Tibetan Plateau-Himalaya transition from ~83°E – 86.5°E.