The study investigated whether short-term priming supports plant defense against complex metal stress and multiple stress (metals and salinity) in halophyte Lobularia maritima (L.) Desv. Plants were pre-treated with ectoine (Ect), nitric oxide donor—sodium nitroprusside (SNP), or hydrogen sulfide donor—GYY4137 for 7 days, and were transferred onto medium containing a mixture of metal ions: Zn, Pb, and Cd. To test the effect of priming agents in multiple stress conditions, shoots were also subjected to low salinity (20 mM NaCl), applied alone, or combined with metals. Hydropriming was a control priming treatment. Stress impact was evaluated on a basis of growth parameters, whereas defense responses were on a basis of the detoxification activity of glutathione S-transferase (GST), radical scavenging activity, and accumulation of thiols and phenolic compounds. Exposure to metals reduced shoot biomass and height but had no impact on the formation of new shoots. Priming with nitric oxide annihilated the toxic effects of metals. It was related to a sharp increase in GST activity, glutathione accumulation, and boosted radical scavenging activity. In NO-treated shoots level of total phenolic compounds (TPC) and flavonoids remained unaffected, in contrast to other metal-treated shoots. Under combined metal stress and salinity, NO and H2S were capable of restoring or improving growth parameters, as they stimulated radical scavenging activity. Ect and H2S did not exert any effect on metal-treated shoots in comparison to hydropriming. The results revealed the stimulatory role of nitric oxide and low doses of NaCl in combating the toxic effects of complex metal stress in L. maritima. Both NO and NaCl interfered with thiol metabolism and antioxidant activity, whereas NaCl also contributed to the accumulation of phenolic compounds.