But it faces stiff competition from critically-acclaimed AMC thriller "Breaking Bad," which many are tipping to win the evening's top prize for best drama on its fifth nomination.
Terror-themed thriller "Homeland" and multiple-Emmy winning "Mad Men" are also in the running for best drama, while "American Horror Story: Asylum" has the most nominations of all, with 17 nods at the awards gala in Los Angeles.
"Game of Thrones" comes next in overall number of nominations with 16, while "Breaking Bad" has 13. On the comedy front, "30 Rock" leads with 13 nods, followed by "Modern Family" with 12 and "The Big Bang Theory" at eight.
Elton John will make his first ever appearance at the show in a tribute to piano legend Liberace, the subject of acclaimed biopic "Behind the Candelabra," which has 15 nominations overall.
Among the frontrunners, Spacey -- scheming congressman Francis Underwood in "House of Cards" -- is vying for best actor against Bryan Cranston, as shy chemistry teacher turned crystal meth drug lord Walter White in "Breaking Bad," the finale of which airs next week.
Others tipped in the male drama race include Briton Damian Lewis in "Homeland" and Jon Hamm of "Mad Men," who surprisingly has never won a Primetime Emmy himself.
For best drama actress, the frontrunners include Kerry Washington of ABC's political thriller "Scandal," who would become the first African-American actress to take that prize.
She is up against Claire Danes as bipolar CIA agent Carrie Mathison in "Homeland," as well as "House of Cards" co-star Robin Wright, who plays Spacey's character's wife Claire.
The series' success highlights the radical changes underway in the TV industry, with more and more viewers "cutting the cable" and watching favorite shows via the Internet on cellphones, tablets and so-called "smart TVs."
"House of Cards," inspired by a BBC series from the early 1990s, was made exclusively for Netflix, the online movie streaming website, which put all 13 episodes online in February in one fell swoop.
Other nominees for best drama include "Downton Abbey" and "Game of Thrones" -- marking the first time no series from a mainstream US television network has been nominated in the category.
Up for best comedy are "Modern Family," "The Big Bang Theory," "Girls," "Louie," "Veep" and "30 Rock," which after seven seasons aired its final episode on NBC in January.
Nominated for best TV movie or miniseries are "American Horror Story: Asylum," "Behind the Candelabra," another HBO music biopic "Phil Spector," "Political Animals," "Top of the Lake" and the History Channel's "The Bible."
"Sopranos" star James Gandolfini, who died in June aged 51, and late "Glee" actor Cory Monteith will be remembered among others who passed away this year, in the three-hour show's "In Memoriam" segment.
Sunday night's show was to start at 5:00 pm (0000 GMT Monday) at LA's Nokia Theatre.
--------------------------------------------------------------------------------------------