This paper studied the effects of two welding modes, i.e., keyhole penetration and full penetration, on laser welding of two zinc-coated steel stack-ups of the same total sheet thickness but different sheet thickness combinations. The effects of welding modes on keyhole and spatter behavior were studied. It was found that keyhole penetration welding led to little spatter and mass loss for a thick-gage stack-up of the same top and bottom sheet thickness (two 1.5 mm zinc-coated steel sheets, viz., Stack-up S). This was confirmed by numerically calculated low Zout values which indicate a low potential of spatter due to zinc outgassing insufficiency. For a stack-up of thin top and thick bottom sheet combination (1.1 mm/1.9 mm, viz., Stack-up D), full penetration mode is more preferred generating less spatter than the keyhole penetration mode. This was attributed to an enlarged keyhole size at the faying interface in the full penetration mode and the relatively thinner top sheet (1.1 mm thick) compared to the bottom sheet (1.9 mm thick). It was confirmed by the low average and maximum values of Zout. In summary, to reduce the spatter in laser welding of zinc-coated steel, the keyhole penetration mode welding is preferred for the stack-up with the top and bottom sheets of similar thickness, and the full penetration mode is more suitable for the stack-up having a much thinner top sheet than the bottom sheet.