Palladino was born in New York City, where she grew up and worked as an actress. Her debut role was as Lo in the critically-acclaimed Manny & Lo opposite Scarlett Johansson, where she played a 16 year old character despite being 14 at the time. The next year she was given her first lead role in the short film Number One Fan with Glenn Fitzgerald, and soon appeared in Wrestling with Alligators with Joely Richardson, the well-received The Adventures of Sebastian Cole with Adrien Grenier, and Second Skin with Fitzgerald again.

The year 2000 saw the release of Palladino's Red Dirt, followed by the independent film Lonesome, and Storytelling with Selma Blair. She then had guest appearances in Law & Order: Criminal Intent, The Sopranos (where she played 2 different characters) and Law & Order.

In 2003, Palladino moved to Los Angeles, married Devon Church at a scenic overlook on Mulholland Drive, and began writing music with her husband as the band Exitmusic. Exitmusic released a debut album in Fall 2007.

In 2004, Aleksa returned to acting with a guest appearance on Medium, followed by her lead role in Spectropia and a supporting one in Find Me Guilty with Vin Diesel. After working in Find me Guilty, the director Sidney Lumet offered Palladino the role of Chris Lasorda in Before the Devil Knows You're Dead, which she kindly accepted. She then filmed The Picture of Dorian Gray, based on the novel by Oscar Wilde, and was landed a supporting lead role in the well-acclaimed Horror sequel Wrong Turn 2: Dead End. Palladino's latest project has been a film entitled Baker, where she plays the lead role of 'Maggie Collins'.