Although the show is set in the Hamptons, most filming actually took place across Long Island, with Oheka Castle in Huntington—about 60 miles west of the Hamptons—serving as the palatial estate of Boris and the exterior of the guest house.

A Long Beach drive-through convenience store called Dairy Barn was dressed up as a fictional hot dog stand for one episode, and Freeport's Nautical Mile served as the exterior and parking lot of Hampton Heritage Hospital.

Oyster Bay Town Hall was transformed into the entrance of the Hamptons Heritage Hospital emergency room, while Huntington Hospital was used for other Hamptons Heritage Hospital scenes.

Downtown Locust Valley stood in for downtown East Hampton in at least one episode, and the North Hempstead Town Hall in Manhasset was used as a police station.

The Catalina Beach Club in Atlantic Beach, New York was redressed for the pilot episode as the fictional Hampt Inn, the hotel where Hank and Evan stay upon their arrival.

Two season-two episodes set in Cuba were actually filmed in Puerto Rico, and the season-five episode 'Lawson Translation' was both set and filmed in Budapest, Hungary.

The pilot was filmed on location on Long Island in spring and fall of 2008 and was directed by Jace Alexander, who had also directed the pilot of Burn Notice, another USA Network show that aired in the hour before Royal Pains.

In July 2010, actor Hayden Christensen and his brother Tove Christensen sued USA Network, claiming they had pitched a similar concierge-doctor show called Housecall; after an initial dismissal was reversed on appeal in 2012, the case was settled in May 2013 with no details made public.

The series premiere drew 5.57 million viewers, the highest series premiere for USA Network since Psych in 2006, and became one of the rare shows in five years to see viewership increase from week two (5.59 million) to week three (6.5 million).