The Afghan-Tajik Depression is a sedimentary basin in the Alpine-Himalayan mountain chain. It is traversed by series of north-south arcuate folds, suggesting that the basin is undergoing east-west compression. A second set of folds in the south of the depression runs east-west, crosscutting those trending north-south. We present results from teleseismic body waveform inversion and depth phase modeling for five recent earthquakes, and from detailed mapping of structures related to active faulting based on satellite imagery and topographic data. We argue that both sets of folds are active and that deformation is vertically partitioned, with north-south compression accommodated on east-west–trending thrust faults within the basement, and east-west compression accommodated on north-south–trending thrust faults above a detachment within the basin fill. The observation that orthogonal shortening can be accommodated simultaneously in this way has several important implications. Juxtaposed orthogonal fold systems identified in the geological record may not require temporally separate events, particularly in gravity-driven fold-and-thrust belts in foreland-basin settings. Pervasive detachment may limit the size of potential earthquakes by preventing single events from rupturing the entire seismogenic layer. However, it may also disguise geomorphic signatures of faulting and interseismic strain accumulation within the lower layer, hindering accurate seismic hazard assessment and regional tectonic interpretations.