He is described by Ephraim George Squier and Edwin Hamilton Davis in their book Ancient Monuments of the Mississippi Valley as a "zealous investigator" in the field of "American antiquarian research.

In 1832 he was stationed at Fort Howard, Wisconsin, and after serving in the Black Hawk War, he resigned his commission on September 30 of the same year.

At this time, he also carefully examined and measured several of the works of the Mound Builders, and his plans and notes of twenty of these remains were embodied in Edwin Hamilton Davis and E. G. Squier's Ancient Monuments of the Mississippi Valley.

At the Battle of Shiloh, he commanded the 3rd brigade of Maj. Gen. Lewis Wallace's division, but failing health compelled his retirement from active service, and he resigned on April 19, 1862.

Whittlesey returned to service in September 1862, serving on Wallace's staff, providing assistance directing civilian and military labor for the defense of Cincinnati.