The casting was announced by Lynne Meadow, the company's artistic director, and Barry Grove, the show's executive producer.
Doug Hughes will helm the production, which will be a part of Manhattan Theatre Club's 2013-2014 Broadway season.
O'Byrne and Messing will play Anthony and Rosemary, "two introverted misfits straddling 40," a synopsis said.
"Anthony has spent his entire life on a cattle farm in rural Ireland, a state of affairs that -- due to his painful shyness -- suits him well. Rosemary lives right next door, determined to have him, watching the years slip away," the synopsis said. "With Anthony's father threatening to disinherit him and a land feud simmering between their families, Rosemary has every reason to fear romantic catastrophe. But then, in this very Irish story with a surprising depth of poetic passion, these yearning, eccentric souls fight their way towards solid ground and some kind of happiness. Their journey is heartbreaking, funny as hell, and ultimately deeply moving."
O'Byrne previously earned a Tony Award nomination for his work in Shanley's play "Doubt," which Hughes directed. O'Byrne won the Tony for Best Featured Actor in a Play for "Frozen," and co-starred on the TV shows "Prime Suspect," "Flash Forward" and "Brotherhood."
"Outside Mullingar" will mark Messing's Broadway debut. The show will play a strictly limited 11-week engagement at MTC's Samuel J. Friedman Theatre in Manhattan.
Previews are to begin Jan. 2 for a Jan. 23, opening night.
Messing is best known for her work on TV's "Smash," "The Starter Wife" and "Will and Grace."
She also appeared in the Manhattan Theatre Club's 1997 off-Broadway production of Donald Margulies' "Collected Stories" opposite Maria Tucci.