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Knowledge of the long-term frequency and intensity of drought events in an area is crucial since drought has adverse effects on natural ecosystems, food security, economy, society, and civilization. We developed a 405 year long (1611-2015C.E.) tree-ring chronology of Pinus wallichiana (Blue pine) from the Dolpo area of the trans-Himalayan region in Nepal to reconstruct drought variability in this remote region. Correlation analysis revealed significant positive relationships with February-August precipitation, but negative correlations with temperature. High positive correlations with the self-calibrated Palmer drought severity index (scPDSI) confirmed that moisture availability during the early growing season and full growing season is the primary limiting factor for Blue pine tree growth in the trans-Himalayan region. We used a linear regression model between our tree-ring record and regional climate data to reconstruct a 319-year long (1697-2015C.E.) February-August scPDSI series. This reconstruction accounts for 39.4% of the total variance in actual sePDSI over the calibration period (1957-2015C.E.). The reconstruction showed that the area was under slightly dry conditions for most of the reconstructed period, with below normal scPDSI values. An extreme drought was observed in the year 1707. Also, the years 1705, 1706, 1784, 1786, 1809, 1810, 1813, 1821, 1849, 1858, 1861, 1909, 1967, 2006, and 2009 experienced severe drought conditions. Consecutive years with moderate drought were 1702-1706, 1783-1789, 1796-1798, 1812-1814, 1816-1827, 1846-1848, 1856-1864, 1873-1877, 1879-1882, 1899-1901, 1908-1911, and 1967-1968. Three historic mega-drought events that occurred in Asia were also captured in our reconstruction: Strange Parallels drought (1756-1768), the East India drought (1790-1796), and the late Victorian Great Drought (1876-1878). Very few wet years (1776-1979, 1989, 1991, and 2003) were observed during the reconstruction period. Power spectrum analysis revealed drought variability at frequencies of 2.0-2.5, 3.0, 12.0, and 128 years, suggesting that drought in the region might be linked to broad-scale atmospheric oceanic variabilities such as the El Nino-Southern Oscillation (ENSO) and the Atlantic Multidecadal Oscillation (AMO). The results not only improve our understanding on regional drought variability, but are also helpful to make decisions on adaptation measures for protecting the marginal communities of the trans-Himalayan region from the anticipated adverse impacts of future droughts.