The UK said it would establish the 834,000-sq-km (322,000-sq-mile) zone around the Pitcairn Islands in the Pacific in 2015.
Data gathered by the drone will be beamed back to a satellite watch room to help prosecute unauthorised trawling.
The drone will patrol areas in the reserve designated as no-fishing zones.
The drone, made by US firm Liquid Robotics, will be directed by staff at the satellite watch room which is monitoring fishing vessels. The craft is equipped with a camera that can take snaps of fishing vessels that are in restricted areas, and satellite technology that can pinpoint their location. The unmanned craft starting patrolling late last month.
The Liquid Robotics drone, called a Wave Glider, is a two-part craft made up of an instrument-bearing boat that floats on the ocean surface that is tethered to a submersible. The craft uses the differential motion between the sea surface and the region the submersible traverses to propel itself.
The self-propelling propulsion system means the Wave Glider can stay at sea for months at a time.
The UK said it established the marine-protected area in the Pitcairns in 2015 and, at the same time, created a watchdog organisation that would try to protect its abundant sea life from fishing.
The seas around the Pitcairns are believed to be home to more than 1,200 species of fish, marine mammals and birds - some of which are unique to the region. It also supports the world's deepest and most well-developed coral reef.
The watch room to oversee the region has been created in the Harwell science park in Oxfordshire with funding from the UK government and the Swiss Bertarelli Foundation and the Pew Charitable Trusts.
An ocean-going drone will be helping to spot illegal fishing in the world's largest, continuous marine reserve.