Now they trail the series 3-1, and face elimination if they lose Game 5 on Sunday. Meanwhile, the Cleveland Indians moved within one victory of their first championship since 1948.
Cleveland can win it all Sunday night, when Trevor Bauer starts for the Indians and Jon Lester for the Cubs.
On Saturday, Indians pitcher Corey Kluber limited Chicago to five hits in six innings, becoming the first pitcher to win Games 1 and 4 since Cincinnati's Jose Rijo in 1990.
Carlos Santana's homer off John Lackey and a run-scoring throwing error by third baseman Kris Bryant on Kluber's infield hit gave Cleveland a 2-1 lead in the second.
Francisco Lindor added an RBI single in the third, Lonnie Chisenhall hit a sacrifice fly in the sixth off Mike Montgomery, and Chicago native Kipnis blew open the game with a three-run homer against Travis Wood in the eighth.
Crestfallen fans quickly cleared out of Wrigleyville, where 1,000 officers were expected to blanket the neighborhood this weekend. Security remained tight with many streets blocked off and alcohol prohibited, except for residents who live in the area.
Outdoor seating at many bars and restaurants were removed, and private security was hired. Many venues only served alcohol in plastic containers.
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Fans came early to Wrigley. By mid-afternoon, the blocks outside the 102-year-old ballpark were a sea of blue. Fans carried "W" signs and took selfies near the famed marquee and statues of the late Harry Caray, Ernie Banks and Ron Santo, cherished figures in Cubs lore who would have loved nothing more than to be part of this.
There were red roses near the feet of all three. There were also four green apples on Caray's statue - three on top of the base and one in his left hand - in a fitting tribute. After all, the famed broadcaster promised after the final game in 1991: "Sure as God made green apples, someday, the Chicago Cubs are going to be in the World Series - and maybe sooner than we think."
VINCE VAUGHN PUMPS UP THE CROWD
Vince Vaughn was the guest conductor for "Take Me Out to the Ball Game" during the seventh-inning stretch.
Vaughn paid tribute to long-time Cubs announcer Harry Caray's rendition of the seventh inning stretch, including the encouragement: "Let's get some runs."
The 46-year-old Vaughn, known for his roles in "Swingers," "Wedding Crashers," and "Old School," has fond memories of watching the Cubs while growing up in the Chicago area.
"I love this. This is my childhood team," he said. "I remember being a kid and us getting out of class to watch the '84 team when we were playing the Padres (in the NL Championship Series). That was fun."
Actor and comedian Bill Murray led the crowd in a rousing version of "Take Me Out To The Ball Game" during the seventh-inning stretch on Friday night.
Murray, a huge Cubs fan, reminded the crowd of 41,703 that it was the last chance to buy beer, and then said they were there to win games rather than drink. He then sang "Take Me Out To The Ball Game" as the cartoon character Daffy Duck.
Also in attendance on Saturday was retired Supreme Court Justice John Paul Stevens, 96. Justice Stevens grew up in Chicago and he actually attended the first World Series game ever played at Wrigley Field way back in 1929.
The Associated Press contributed to this report.