Urquiola was involved in nearly every aspect of the design for the Hotel Il Sereno, from its architecture and bedroom furnishings to its staff uniforms and private boats.
The 30-suite hotel is the third property from luxury group Sereno Hotels, which also operates Villa Pliniana, a 16th-century palazzo nearby.
Il Sereno is one of few contemporary properties in the exclusive holiday spot, which Sereno Hotels describes as not having seen any new hotel construction in decades, and is built on top of an existing arched stone boathouse.
"It's a place with incredible history," Urquiola told Dezeen. "To do a new building on the lake in a contemporary way is not easy."
"It took a lot of serious conversations with the mayor and the authorities. The process was slow. We spoke to six different authorities."
Urquiola joins the small number of designers to have entered the world of large-scale architecture with the project, which saw her create elements such as the hotel's central staircase.
Made of walnut wood and bronze, the stacked squares making up the steps appear to float free of one another as they wind up to the first floor.
Other materials that recur throughout the space include copper, traditional Venetian terrazzo and travertine stone.
In the bedrooms, lobby and hotel restaurant, Urquiola assembled earth-toned furniture with splashes of pastel pink and bolder shades of green.
As well as pieces from her past collections and lighting by Flos, the hotel includes some furniture custom made for the space.
Urquiola's interiors can also be experienced inside Il Sereno's private boats, which ferry guests around Lake Como. The three custom wooden Cantiere Ernesto Riva boats are made by the namesake family that has been building them by hand in the nearby town of Laglio since 1771.
Plantings both inside and outside of the hotel were designed by vertical gardens pioneer Patrick Blanc, who created two living walls and one "green sculpture".
The outside areas of Il Sereno also incorporate an infinity pool with views to the Italian Alps and the surrounding small towns.
Urquiola's influence extends to the staff uniforms, which feature locally produced silk scarves of her design. A similar version is made available for guests to purchase.
Il Sereno is among the most wide-ranging projects from the Milan-based designer, who has a long-standing connection to Italy and recently took over the art direction of the major Italian furniture brand Cassina.
She has recently created the interiors for another of the country's hotels, Room Mate Giulia in Milan, whose rooms feature a colour clash of Cassina furnishings.
Photography is by Patricia Parinejad