Abstract: Land salinization leads to reduction in crop yield and degradation of soil environment. Nanomaterials (NMs), emerging for nano-based agriculture, have great potential to improve plant saline tolerance. However, there is a lack of knowledge of the molecular mechanisms of the nano-stimulated plant saline tolerance. In this study, salt-stressed (100 mmol/L NaCl) tobacco (Nicotiana tabacum L.) BY-2 cell suspensions were exposed to nano-TiO₂ (nTiO₂) or nano-Se (nSe), and cell viability was measured to evaluate the salt tolerance induced by nanomaterials. Non-invasive Micro-test Technology (NMT) was used to detect the net flux of Na⁺, and liquid chromatography-tandem-mass spectrometry (LC-MS/MS) was used to reveal the effects of nanomaterials on the metabolomics of tobacco BY-2 cell suspensions under salt stress. The results showed that: (1) 0.1 mg/L nTiO₂ (6 h) and 0.5 mg/L nSe (12 h) significantly increased the viability of salt stressed tobacco BY-2 cell suspensions at 6 h (8.1%) and 12 h (13.6%), respectively. (2) 0.1 mg/L nTiO₂ (6 h) and 0.5 mg/L nSe (12 h) also significantly increased the extrusion of Na⁺ by 171.5% and 99.0%, respectively. (3) At the metabolomics level, different metabolic pathways were involved in nTiO₂ or nSe-regulated salt tolerance of tobacco BY-2 cell suspensions. Specifically, exposure to 0.1 mg/L nTiO₂ for 6 h or 0.5 mg/L nSe for 12 h of led to alterations in 53 and 73 different metabolites, respectively. nTiO₂ enhanced the synthesis of many different classes of metabolites (some amino acids and peptides, fatty acids and conjugates, tricarboxylic acid cycle (TCA cycle) organic acids, sugars and pyrimidines, etc.), while nSe mainly increased the synthesis of amino acids and peptides, indole and salicylic acid. (4) In addition, in salt-stressed tobacco BY-2 cell suspensions exposed to nTiO₂, the amounts of uridine, pyridoxal, mannose, hordenine and trigonelline were significantly correlated with Na⁺ efflux. Meanwhile, the amounts of indoleacrylic acid, tryptophan, phenylalanine, tyrosine and acetylarginine were significantly correlated with Na⁺ efflux after nSe exposure, implying that the shikimic acid pathway could contribute to the nSe-induced salt tolerance. These findings show that nTiO₂ and nSe improve plant salt tolerance by different metabolic pathways.