Born in New York City, Makkena started her acting career in 1986 and appeared in the TV show Santa Barbara. She later landed her first movie role in Eight Men Out. She has made various guest appearances in TV shows such as Law & Order, Monsters, NYPD Blue, House, and NCIS.
In 1992 she landed a starring role in the popular movie Sister Act as the shy but talented singing nun Sister Mary Robert (although her singing voice was dubbed by Andrea Robinson), a role she reprised in Sister Act 2: Back in the Habit the following year.
She appeared in various other television roles until 1997, when she starred in Air Bud, followed by the independent film Finding North. She continued appearing on television shows such as The Job, Oliver Beene, and Listen Up!
She made a guest appearance on House in 2007. She also made a guest appearance on Law & Order: Special Victims Unit in 2009.
Makkena also appeared on the pilot episode of Chuck as an unnamed National Intelligence Director. Some casting lists have her appearing as General Mary Beckman, a rank and surname that would be re-used in future episodes for the recurring character of NSA director Gen. Diane Beckman. The actress in that role, Bonita Friedericy, believes both Beckmans to be the same character. Additionally, Beckman's identification card, shown on "Chuck's Chart" (first seen in the second season episode, "Chuck Versus the Lethal Weapon", and clearly referring to Friedericy's character by its reference to her relationship with Roan Montgomery) reads "Gen. M. Beckman".
Among her Broadway credits are Lend Me a Tenor (1989) and Side Man (1998).
She also guest-starred in NCIS as Dr. Rachel Cranston, a psychologist conducting evaluations on Gibbs and his team. She was later revealed to also be the elder sister of the deceased Caitlin Todd.
Makkena has been married since 1997, has one child and lives in New York City.