Mota Maradi is a sorghum line that exhibits holistic salinity tolerance mechanisms, making it a viable potential donor in breeding efforts for improved sorghum lines. High soil salinity is one of the global challenges for crop growth and productivity. Understanding the salinity tolerance mechanisms in crops is necessary for genetic breeding of salinity-tolerant crops. In this study, physiological and molecular mechanisms in sorghum were identified through a comparative analysis between a Nigerien salinity-tolerant sorghum landrace, Mota Maradi, and the reference sorghum line, BTx623. Significant differences on physiological performances were observed, particularly on growth and biomass gain, photosynthetic rate, and the accumulation of Na+, K+, proline, and sucrose. Transcriptome profiling of the leaves, leaf sheaths, stems, and roots revealed contrasting differentially expressed genes (DEGs) in Mota Maradi and BTx623 which supports the physiological observations from both lines. Among the DEGs, ion transporters such as HKT, NHX, AKT, HAK5, and KUP3 were likely responsible for the differences in Na+ and K+ accumulation. Meanwhile, DEGs involved in photosynthesis, cellular growth, signaling, and ROS scavenging were also identified between these two genotypes. Functional and pathway analysis of the DEGs has revealed that these processes work in concert and are crucial in elevated salinity tolerance in Mota Maradi. Our findings indicate how different complex processes work synergistically for salinity stress tolerance in sorghum. This study also highlights the unique adaptation of landraces toward their respective ecosystems, and their strong potential as genetic resources for future plant breeding endeavors.