High velocity low amplitude spinal manipulation (HVLA-SM) is used frequently to treat musculoskeletal complaints. Little is known about the intervention’s biomechanical characteristics that determine its clinical benefit. Using an animal preparation, we determined how neural activity from lumbar muscle spindles during a lumbar HVLA-SM is affected by the type of thrust control and by the thrust's amplitude, duration, and rate. A mechanical device was used to apply a linear increase in thrust displacement or force and to control thrust duration. Under displacement control, neural responses during the HVLA-SM increased in a fashion graded with thrust amplitude. Under force control neural responses were similar regardless of the thrust amplitude. Decreasing thrust durations at all thrust amplitudes except the smallest thrust displacement had an overall significant effect on increasing muscle spindle activity during the HVLA-SMs. Under force control, spindle responses specifically and significantly increased between thrust durations of 75 and 150 ms suggesting the presence of a threshold value. Thrust velocities greater than 20–30 mm/s and thrust rates greater than 300 N/s tended to maximize the spindle responses. This study provides a basis for considering biomechanical characteristics of an HVLA-SM that should be measured and reported in clinical efficacy studies to help define effective clinical dosages.