Spencer's Oscar triumph came for her role as a headstrong black maid whose willful ways continually land her in trouble with white employers in 1960s Mississippi.
Spencer wept throughout her breathless speech, in which she apologized between laughing and crying for running a bit long on her time limit.
"Thank you, academy, for putting me with the hottest guy in the room," Spencer said, referring to last year's supporting-actor winner Christian Bale, who presented her Oscar.
Her brash character holds a personal connection: "The Help" author Kathryn Stockett based some of the woman's traits on Spencer, whom she met through childhood pal Tate Taylor, the director of the film.
Before taking the stage, Spencer got kisses from "The Help" co-stars Viola Davis, a best-actress nominee, and Jessica Chastain, a fellow supporting nominee.
"I share this with everybody," whose 15-year career includes dozens of small parts, often as a nurse, in such movies and TV shows as "Seven Pounds," "A Time to Kill" and "The X-Files."
Martin Scorsese's Paris adventure "Hugo" won four Oscars, including the first two prizes of the night, for cinematography and art direction. It also won for sound mixing and sound editing.
It was a great start for Scorsese's film, which led contenders with 11 nominations.
"Marty, you're a genius as usual," said "Hugo" cinematographer Robert Richardson, who won his third Oscar after previous wins for "JFK" and Scorsese's "The Aviator."
Best-picture front-runner "The Artist," which ran second to "Hugo" with 10 nominations, won for costume design.
The Oscars normally start with a major prize such as one of the supporting-acting categories, but this one began with an unusual flurry of technical awards. Meryl Streep's Margaret Thatcher drama "The Iron Lady" claimed the makeup Oscar.
"Thanks, Meryl, for keeping me employed for the last 37 years. Your brilliance makes my work look good, no matter what," said J. Roy Helland, who shared the makeup Oscar with Mark Coulier.
Oscar organizers saved the first acting trophy until nearly a quarter of the way through the 24 awards. But TV viewers had a consolation prize at the outset with the return of beloved Oscar host Billy Crystal.
Crystal got the show off to a lively start with a star-laden montage in which he hangs out with Justin Bieber and gets a nice wet kiss from George Clooney.
Back as Oscar host for the first time in eight years, Crystal also did his signature introduction of the best-picture nominees with a goofy song.
Before his monologue, Crystal appeared in a collection of clips inserting him in scenes from key nominees. The montage included re-creations from some 2011 films featuring Tom Cruise of "Mission: Impossible - Ghost Protocol" and Clooney's best-picture contender "The Descendants," with the actor planting a kiss on Crystal.
Spoofing a scene from nominee "Midnight in Paris," Bieber told Crystal he was there to bring in the 18-to-24-year-old demographic for the 63-year-old host.
Crystal's return as host seemed appropriate on a night that had Hollywood looking back fondly on more than a century of cinema history.
The top two nominees - "Hugo" and "The Artist" - are both love songs to early cinema.
"Hugo" centers on a mystery connected to French cinema pioneer Georges Melies, who made groundbreaking fantastical short films in the early 1900s. "The Artist" traces the downfall of a 1920s movie star and is favored to become the first silent film to win best picture since the original Oscar ceremony 83 years ago.
Add the Marilyn Monroe tale "My Week with Marilyn" - which earned Michelle Williams a best-actress nomination as the Hollywood's greatest sex goddess and Kenneth Branagh a supporting-actor nomination as Oscar winner Laurence Olivier - and the show's producers had a ready-made script for a night of fond recollection and backslapping about show business.
Producers Brian Grazer and Don Mischer created the right setting, converting the theater where the Oscars have been held for the last decade into a grand mock-up of a stylish old movie house.
Of course, nostalgia can be sad along with celebratory. The Eastman Kodak Co., whose film has been a staple in the business for as long as Hollywood has been around, is in bankruptcy, and to save money, it won court approval to duck out of its sponsorship deal for the theater that's home to the Oscars.
The signs were still up identifying it as the Kodak Theatre, but at the request of the landlord, Oscar organizers yanked references to it from the broadcast.
Stars such as Clooney, Streep, Brad Pitt and Jean Dujardin arrived on the red carpet to the delight of fans in the bleachers outside the theater, but comedian Sacha Baron Cohen showed up and upset the chic Hollywood tone.
Cohen arrived dressed in an over-the-top white military uniform, sunglasses and a thick beard to promote his upcoming film "The Dictator." Holding an urn he jokingly claimed were the ashes of North Korean dictator Kim Jong Il, Cohen then dumped the container onto "American Idol" host Ryan Seacrest.
Among key nominees, Dujardin had a chance to become the first Frenchman to win best actor for "The Artist."
Christopher Plummer is in line to become the oldest acting winner ever at 82. Streep might join the acting three-peat club with a third Academy Award as Thatcher in "The Iron Lady."
Because of a change in voting rules, the Oscars feature nine best-picture nominees for the first time, instead of the 10 they had the last two years.
Competing against "The Artist" and "Hugo" for the top honor are Clooney's family drama "The Descendants"; the Deep South tale "The Help,"; the romantic fantasy "Midnight in Paris," from writer-director Woody Allen; Brad Pitt's baseball tale "Moneyball" and his family saga "The Tree of Life"; the World War I epic "War Horse," directed by Steven Spielberg; and Tom Hanks and Sandra Bullock's Sept. 11 story "Extremely Loud & Incredibly Close."
The record-holder with 17 acting nominations, Streep has won twice and would become only the fifth performer to receive three Oscars. Jack Nicholson, Ingrid Bergman and Walter Brennan all earned three, while Katharine Hepburn won four.
It's been almost three decades since Streep last received an Oscar, for 1982's "Sophie's Choice." Though she has the most acting nominations, she also has the most losses - 14. Another loss would be her 13th in a row.
Streep has tough competition in Davis, her co-star in 2008's "Doubt," who also was up for best actress as a maid leading the fight to expose racism in "The Help."
Best actor also looks like a two-person contest between Clooney as the distressed patriarch of a Hawaiian clan in "The Descendants" and Dujardin as a silent-era superstar whose career tanks as talking pictures take over in "The Artist."
It would be the second Oscar for Clooney, who won the supporting-actor prize for 2005's "Syriana." While French actresses have won before, among them Marion Cotillard and Juliette Binoche, Dujardin would be the first actor from France to receive an Oscar.
Dujardin was picked as best actor Saturday at the Spirit Awards honoring independent film, where "The Artist" ruled with four prizes, including best picture and director for Michel Hazanavicius, who is favored for the same trophy at the Oscars.