Biogenic VOC emission estimation dates back to 1960 when Dr. Fritz Went (director of the Missouri Botanical Garden) made a first attempt to quantify biogenic VOC emissions into the atmosphere and estimated that at least 100 million tons of global annual emissions from monoterpene emissions alone. Soon after, Rei Rasmussen, a student of Dr. Went, discovered surprisingly high emissions of isoprene from certain plants and spent the next decade convincing the scientific community that isoprene emissions were real. He then joined the faculty at Washington State University where he developed the first regional estimates of isoprene and monoterpenes from North America. He also collaborated on multiple measurement studies with other WSU Professors (including Hal Westberg and Brian Lamb) and students (including Pat Zimmerman) who became early pioneers in the efforts to develop quantitative BVOC emission estimates. With NOAA funding for investigating "acid rain" Lamb and Westberg, and their graduate students Alex Guenther and David Gay, built a US biogenic emission model based on earlier work by Zimmerman. In 1990, USEPA scientist Tom Pierce used this model as the starting point for the Biogenic Emission Inventory System (BEIS). Guenther graduated from WSU and joined Zimmerman at the National Center for Atmospheric Research (NCAR) and worked on improving the BVOC emission estimates including on the global scale for the Global Emissions Inventory Activity led by Tom Graedel of AT&T Bell Laboratories. NCAR and EPA scientists, including Pierce and Chris Geron, collaborated on improving the BEIS model throughout the 1990s.

MEGAN was originally written in 2002 as a Visual Basic (within ACCESS) code by Alex Guenther and used internally at NCAR. The Visual Basic code was converted into a "stand-alone" FORTRAN code by Jack Chen, a WSU graduate student so that it could be used with regional air quality modeling. Guenther and colleagues continued to improve the model and the "stand-alone" FORTRAN code was updated primarily by Tanarit Sakulyanontvittaya (PhD student at University of Colorado). This version of the code (MEGAN v2.04) was released publicly on October 29, 2007 along with all of the driving variables required to run the model. In 2012, Guenther and colleagues integrated new findings and improved parameters and driving variables into a version (MEGAN version 2.10). The "stand-alone" FORTRAN code was updated with programming primarily by Xuemei Wang (Professor at Sun-Yat Sen University) and Tan Sakulyanontvittaya (scientist at ENVIRON). The code was also implemented into CESM/CLM by Collette Heald (MIT), WRF by Serena Chung (WSU), GEOS-Chem by Dylan Millet (U. Minnesota), SOSA by Michael Boy (U. Helsinki) and other CTMs. Single-point versions of MEGANv2.1 (useful for comparing with flux tower data) has also been written in spreadsheet form in Visual Basic (within EXCEL) by Guenther and in MATLAB by Thomas Karl (U. Innsbruck).

Biogenic VOC emissions research and MEGAN development is continuing today at the University of California, Irvine. The MEGAN3.1 beta code was released in 2019 and the version 3.2 is expected in October 2021.