The alloy 2.25Cr-1Mo-0.25V is commonly used for heavy wall pressure vessels in the petrochemical industry, such as hydrogen reactors. As these reactors are operated at elevated temperatures and high pressures, the 2.25Cr-1Mo-0.25V welding consumables require a beneficial combination of strength and toughness as well as enhanced creep properties. The mechanical properties are known to be influenced by several welding parameters. This study deals with the influence of the heat input during submerged-arc welding (SAW) on the solidification structure and mechanical properties of 2.25Cr-1Mo-0.25V multilayer metal. The heat input was found to increase the primary and secondary dendrite spacing as well as the bainitic and prior austenite grain size of the weld metal. Furthermore, it was determined that a higher heat input during SAW causes an increase in the stress rupture time and a decrease in Charpy impact energy. This is assumed to be linked to a lower number of weld layers, and therefore, a decreased amount of fine grained reheated zone if the multilayer weld metal is fabricated with higher heat input. In contrast to the stress rupture time and the toughness, the weld metal’s strength, ductility and macro-hardness remain nearly unaffected by changes of the heat input.