As an adolescent Drebbel was apprenticed to an engraver but soon developed an interest in alchemy and mechanical inventions. In 1598 he was granted a patent for a perpetual motion machine which reportedly used changes in atmospheric pressure to power a clock. This "invention" is thought to have established Drebbel's fame in scientific and aristocratic circles in Europe. Around 1604 he journeyed to England, where he was awarded an annuity by King James I (1566-1625) to continue his scientific work. Drebbel has been credited with constructing the first compound microscope using two sets of convex lenses, and he employed his skill as lens grinder to manufacture a variety of optical instruments.

During the early 1620s Drebbel designed and built his most famous invention, the submarine. Although a similar design had been described some fifty years earlier, Drebbel's is the first known to have been constructed. Consisting mainly of greased leather stretched over a wooden frame, Drebbel's submarine was propelled by oars projecting through the sides and sealed with leather flaps. The vessel was capable of traveling twelve to fifteen feet (3.6 to 4.5 meters) below the surface, and fresh air was supplied by tubes running to the surface with floats at the top. Drebbel successfully tested his submarine several times in the Thames River in England.

Drebbel invented the first thermostat, which used a column of mercury and a system of floats and levers to maintain a steady temperature within a furnace. He later invented an incubator for hatching eggs which used the same principle for temperature regulation. Drebbel also discovered the first permanent scarlet fabric dye, which became popular throughout Europe, and developed a process for manufacturing sulfuric acid from sulfur and saltpeter.