Proso millet (Panicum miliaceum L.) is resilient to abiotic stress, especially to land degradation caused by soil salinization. However, the mechanisms by which its roots adapt and tolerate salt stress are obscure. In this study, plants of a salt-sensitive cultivar (SS 212) and a salt-tolerant cultivar (ST 47) of proso millet were exposed to severe salt stress and subsequent re-watering. ST 47 exhibited greater salt tolerance than SS 212, as evidenced by higher increases in total root length (TRL), root surface area (RSA), root tip number (RTN). Moreover, microstructural analysis showed that relative to SS 212, the roots of ST 47 could maintain more intact internal structures and thicker cell walls under salt stress. Digital RNA sequence analysis revealed that ST 47 maintained better Na+/K+ balance to resist Na+ toxicity via a higher capability to restrict Na+ uptake, vacuolar Na+ sequestration, and Na+ exclusion. The mechanism for Na+ toxicity resistance in ST 47 involved promoting cell wall composition changes via efficient regulation of galactose metabolism and biosynthesis of cellulose and phenylpropanoids. Overall, this study provides valuable salt-tolerant cultivar resources and mechanisms for regulating salt tolerance, which could be applied for the rehabilitation of saline lands. Display omitted •Salt-tolerant proso millet cultivar exhibits faster recovery after re-watering then the susceptible cultivar.•Salt-tolerant cultivar maintains complete root structure and regulates Na+, K+ balance to enhance salt tolerance.•Salt-tolerant cultivar modulates cell wall components by affecting its biosynthesis pathway to resist salt stress.