High-efficient disaggregation of palygorskite (PAL) crystal aggregates into individual nanorods is the key to exploiting its nanometer properties, which remains a challenge at present. The sonochemical cavitation effects have been successfully employed for the intensification of physical and chemical processing applications, but it still lacks the relevant study on the scale-up disaggregation of PAL crystal bundles. Here, the energy-efficient, scale-up ultrasonic process was developed to disaggregate PAL aggregates in batches, and the effects of ultrasonic treatment time, temperature, and power on physicochemical features of PAL were systematically investigated. The results showed that the single dispersed PAL nanorods could be continuously produced by sonicating 15 wt% of PAL suspension at 20 kHz, 2000 W and 30 °C for 5 min retaining the original nanorod length and layered-chain structure. It also greatly improved the dispersion of nanorod crystal, specific surface area and suspension stability of PAL. The ultrasonically disaggregated PAL has a higher pulping rate in water (14.96 m3/t) and saturated NaCl system (14.45 m3/t), which is significantly better than that of natural PAL in water (14.72 m3/t) and saturated NaCl solution (12.37 m3/t). It suggests that the disaggregated PAL exhibits excellent potential and adaptability as a viscosity enhancer for drilling fluid. Therefore, this work provides a feasible and efficient ultrasonic process for large-scale industrialized disaggregation of PAL crystal bundles, laying a foundation for the high-value utilization of natural PAL as one-dimensional nanomaterials.