| Honorific-Prefix: | Capitán |
| Domingo de Acassuso y de los Terreros | |
| Order: | Alcalde of 2nd vote of |
| Office: | Buenos Aires |
| Term Start: | 1716 |
| Term End: | 1717 |
| Predecessor: | Antonio de Igarzábal y Goitia |
| Successor: | Mathías Solana |
| Birth Date: | 1658 |
| Birth Place: | Biscay, Spain |
| Death Date: | 1727 |
| Death Place: | Buenos Aires, Argentina |
| Restingplace: | Parish of San Nicolás de Bari |
| Nationality: | Spanish |
| Occupation: | politician merchant |
| Profession: | Army's officer |
| Signature: | Domingo de Acassuso, firma.jpg |
| Allegiance: | Spain |
| Branch: | Spanish Army |
| Serviceyears: | 1680-c.1720 |
| Rank: | Captain |
| Unit: | regiments of Seville and Río de la Plata |
Domingo de Acassuso (1658–1727) was a Spanish politician and military man, who served as mayor of Buenos Aires in 1716. He was the founder of the city of San Isidro in Buenos Aires Province.
He was born in Zalla, province of Biscay, the son of Domingo de Acassuso and María de los Terreros. He was married to Teresa de Pessoa, daughter of Alejo de Pessoa y Figueroa, a descendant of families Gonçalves-Nuñez Cabral de Melo, and Juana Gómes, a mulatto woman, from whose union with the Pessoa family, descend a large number of patrician families of Buenos Aires. Established in Buenos Aires fulfilled various political and military roles, including treasurer and accountant, and the vice-mayor of the city. His most important work was related to the construction of the Church of San Nicolás de Bari. He also was involved in the slave trade of Buenos Aires with the French and English factories. His house was located in the vicinity of the Real Asiento de Inglaterra, a factory belonging to South Sea Company.
The Club Atlético Acassuso was founded in honor of Domingo de Acassuso. His family was linked to the family of Domingo Pelliza, a politician and military man, born in La Spezia region of Liguria, Italy.