When he was only 10 years old, Jesse Santos painted a mural that was placed in front of the town church. He began drawing professionaly at age 15. He did portraits of the American GI's and Japanese soldiers that occupied his hometown. He was working as a sidewalk portrait artist, when he was noted by cartoonist Tony Velasquez. Santos began his comics career in 1946 with the 'Kidlat' feature in Halaklak, the first Filipino comic book. Santos then joined Pilipino Komiks to create the detective strip 'DI 13' together with Damy Velasquez. The series became the country's most famous detective comic, and also knew several spin-offs, such as 'DI Jr, and even a movie adaptation.
Santos was the chief artist for Paraluman magazine, staff artist for Gold Star Publishing, Ace Publications, Graphic Arts Inc. and G. Miranda & Sons Publishing Co. He cooperated with Mars Ravelo, Pablo Gomez, Greg Igna De Dios, Mauro Cabuhat and Larry Tuazon on such comic book serials as 'Inspirasiyon', 'Boksingerea', 'Dambanang Putik', 'ROTC', 'Paula', 'Tomador' and 'Dar Aguila'. Santos moved to the United States in 1969, where he began an association with Western Publications in 1970. He did the book illustrations for 'Davy Crockett', and illustrated Gold Key titles like 'Brothers of the Spear', 'Dagar', 'Dr. Spektor' and 'Tragg'. He also worked for 'Mystery Digest' and 'Red Circle Comics'. He was also active as a painter.