Panicum antidotale, a C4 monocot, has the potential to reclaim saline and drylands and to be utilized as fodder and forage. Its adaptability to survive saline stress has been proven with eco-physiological and biochemical studies. However, little is known about its molecular mechanisms of salt tolerance. In this study, an integrated transcriptome and proteome analysis approach, based on RNA sequencing and liquid chromatography tandem mass spectrometry (LC-MS/MS), was used to identify the said mechanisms. Plants were treated with control (0 mM), low (100 mM), and high (300 mM) sodium chloride (NaCl) treatments to distinguish beneficial and toxic pathways influencing plant biomass. The results indicated differential expression of 3,179 (1,126 upregulated/2,053 downregulated) and 2,172 (898 upregulated/1,274 downregulated) genes (DEGs), and 514 (269 upregulated/245 downregulated) and 836 (494 upregulated/392 downregulated) proteins (DEPs) at 100 and 300 mM NaCl, respectively. Among these, most upregulated genes and proteins were involved in salt resistance strategies such as proline biosynthesis, the antioxidant defense system, ion homeostasis, and sugar accumulation at low salinity levels. On the other hand, the expression of several genes and proteins involved in the respiratory process were downregulated, indicating the inability of plants to meet their energy demands at high salinity levels. Moreover, the impairments in photosynthesis were also evident with the reduced expression of genes regulating the structure of photosystems and increased expression of abscisic acid (ABA) mediated pathways which limits stomatal gas exchange. Similarly, the disturbance in fatty acid metabolism and activation of essential ion transport blockers damaged the integrity of the cell membrane, which was also evident with enhanced malondialdehyde (MDA). Overall, the analysis of pathways revealed that the plant optimal performance at low salinity was related to enhanced metabolism, antioxidative defense, cell growth, and signaling pathways, whereas high salinity inhibited biomass accumulation by altered expression of numerous genes involved in carbon metabolism, signaling, transcription, and translation. The data provided the first global analysis of the mechanisms imparting salt stress tolerance of any halophyte at transcriptome and proteome levels.