After attending Isidore Newman School in New Orleans, Plotkin worked at Harvard University's Museum of Comparative Zoology when he joined an expedition searching for an elusive crocodilian species in 1978 and was galvanized into returning to education.

He completed his bachelor of liberal arts degree at Harvard University's Harvard Extension School, his master's degree in forestry at Yale School of Forestry, and his Ph.D. at Tufts University; during which he completed a handbook for the Tiriyó people of Suriname detailing their own medicinal plants—the only other book printed in Tiriyó language being the Bible.

In 1995, Plotkin and prominent Costa Rican conservationist Liliana Madrigal formed the Amazon Conservation Team[1] to protect Amazonian rainforest in partnership with local indigenous peoples.

Plotkin received the San Diego Zoo Gold Medal for Conservation (1993) and the Roy Chapman Andrews Distinguished Explorer Award (2004).

Time called him an "Environmental Hero for the Planet" (2001) and Smithsonian hailed him as one of "35 Who Made a Difference" (2005), along with other notables like Bill Gates, Steven Spielberg, and fellow New Orleanian Wynton Marsalis.

The degree citation read in part: "For teaching us that the loss of knowledge and species anywhere impoverishes us all; for combining humanitarian vision with academic rigor and moral sensibility; and for reminding us always, with clarity and passion and humor, that when we study people and plants, we are simultaneously exploring paths to philosophy, music, art, dance, reverence, and healing; Lewis and Clark is honored to confer on you today the Doctorate of Humane Letters, honoris causa."

In 2019, the Harvard University Extension School gave him the Shinagel Award for Public Service “in recognition of his lifelong commitment to the protection of the Amazon rainforest and the tribal communities within.

He details discoveries already providing leads in the laboratory: pain-killers from the skin of rainforest frogs, anti-coagulants from leech saliva, and anti-tumor agents from snake venom.

Medicine Quest also provides background on the centuries-old pursuit of cures, ranging from the ancient Egyptians' expeditions in search of healing plants, to the 19th-century development of aspirin from willow bark and the extraction of penicillin from fungi.