San Isidro was the capital of Nueva Ecija from 1850 to 1917. In 1896, the revolucionarios from Cabiao secretly marched to San Isidro to attack the Spanish provincial government. Today the victory is known as the First Cry of Nueva Ecija, the province is recognized as one of the first of the eight provinces that revolted against Spain.
The Wright Institute, established in 1903 in San Isidro, was one of the first high schools established outside Manila during the American period.
The town was occupied by Japanese troops in 1942, during the second world war. The combined U.S. and Philippine Commonwealth ground forces liberated San Isidro and defeated the Japanese forces in 1945 during the end of the war.
The Crispulo Sideco (also known as Kapitang Pulong) house was built in the 19th century. Built in the Floral period in the Philippine colonial architecture, ogee arches, filigreed wooden panels, grilles wrought in curlicues and floral and foliate designs abound in the house as basic structural elements or as ornaments.