Nemesis is the first entry in the long-running Gradius series on Game Boy. Its side-scrolling shoot'em up gameplay follows the series template closely. Players control the Vic Viper through five levels, most based on levels in earlier entries, for a kind of 'greatest hits' of the series. There is a cave level, the mandatory Moai stage, an organic level with Gigeresque designs, a graveyard (similar to bonus stages in earlier versions), and a high-tech base. Besides the classic core ship in the first level, all boss enemies are entirely new.
The gameplay involves collecting power-ups through a cycling system: collected power ups advance the power meter which can be activated at any time to gain the highlighted item. The line-up includes speedups, missiles, dual shots, lasers, option satellites, and forcefields. Players have the flexibility to start in any of the five levels and set the number of lives up to 99.