The organ of Santiago Tlazoyaltepec is one of a group of six 2´ table organs that are nearly identical in construction. It is one of the most significant organs in Oaxaca, because a label inside the case cites not only the date of construction, 1724, but also the name of the organ builder, Marcial Ruis (Ruiz) Maldonado. The case, table, and bellows box still retain their original baroque decoration. The flat planes of the organ case are painted with images of religious figures: on the left side, Saint Peter; left door exterior, Apostol Saint James (Santiago); left door interior, an angel musician playing a bassoon; on the right door interior, an angel musician playing a viola da gamba; right door exterior, Saint John the Evangelist; right side, Saint Paul; back panel, King David playing a harp. The eyes and mouth of King David and one of the angels surrounding him (also in the small Coixtlahuaca organ) were scraped off; the reason is a mystery. The top cover of the organ is missing. The first pallet is marked with a Maltese cross. 

The organ was kept in good repair and played regularly. Labels inside the case cite an intervention in 1871 by José de Jesús Cano of the Cano family of organ builders and by the unknown organbuilder José Domingo León (label incomplete with no date). The organ is located in a rustic choir loft with a dirt floor and a ladder for access. Since the community invested in its maintenance and use, the organ may once have been in a more visible location in the church. At some point while the organ was still in use, the accessory stops were canceled, and their slider tabs were removed. Once it was no longer used and the pipes and keyboard had been removed, it may have been moved up to the choir loft. The interior of the organ was damaged in 2013 when a reflector lamp, left face down inside the case after a community celebration, was inadvertently turned on. It burned through a pile of old religious books and destroyed much of the windchest. Luckily, the smoke alerted the authorities, and the fire was extinguished before it ignited the entire organ and spread to the wooden roof of the church itself.