Following graduation, Whitney accepted a tutoring position in South Carolina but ended up traveling to Georgia instead. The trip was initiated by meeting Phineas Miller, who suggested he visit Mulberry Grove Plantation near Savannah, owned by Catherine Greene, the widow of General Nathanael Greene.

While at Mulberry Grove, Whitney observed the labor-intensive process of separating cotton fibers from seeds. He quickly conceived of and built a machine to automate this process, drastically increasing the efficiency of cotton production. The cotton gin's invention was a watershed moment.

Whitney obtained a patent for his cotton gin, granting him exclusive rights to manufacture and profit from the invention. However, widespread infringement and difficulties in enforcing the patent would soon plague his business ventures.

Despite the patent, the cotton gin was widely copied and manufactured illegally across the South. Whitney and Miller spent years engaged in costly and largely unsuccessful legal battles to protect their patent rights. This proved to be a frustrating and financially draining experience.

Whitney's original cotton gin patent was set to expire. He worked to get a new patent design approved. This was the start of a long battle that would ultimately be successful, giving him the exclusive rights to his design and production of the cotton gin.