The ongoing 22 year drought in the Upper Colorado River Basin (UCRB) has been extremely severe, even in the context of the longest available tree-ring reconstruction of annual flow at Lees Ferry, Arizona, dating back to 762 CE. While many southwestern drought assessments have been limited to the past 1200 years, longer paleorecords of moisture variability do exist for the UCRB. Here, gridded drought-atlas data in the UCRB domain along with naturalized streamflow data from the instrumental period (1906–2021) are used in a K nearest neighbor (KNN) nonparametric algorithm to develop a streamflow reconstruction for the Lees Ferry gage starting in 1 CE. The reconstruction reveals a 2nd century drought unmatched in severity by the current drought or by well-documented medieval period droughts in the UCRB. Although data are sparse, analysis of individual long tree ring records and other paleoclimatic data also support the occurrence of an exceptional 2nd century drought.