The attack in Mexico's second-largest municipality took place just hours after a shootout between soldiers and presumed cartel gunmen left eight people, including an innocent driver, dead in the northeastern city of Monterrey. Monterrey is Mexico's third-largest city.
In the Guadalajara attack, assailants in a Jeep Cherokee and a taxi drove up to the Butter Club, located in a bar and restaurant district popular with young people, and sprayed it with bullets.
Some of the men then got out of the taxi and threw a grenade into the nightclub entrance, said a police official, who spoke to news media at the scene and left without giving his name. The gunmen fled after the pre-dawn attack, he said.
Three were killed at the scene and three more died later in hospitals, said Medical Services Director Yannick Nordin. A Venezuelan and a Colombian were among the dead.
In a press conference led by state Attorney General Tomas Coronado Olmos, authorities said the attack may have been the result of a fight between two groups hours earlier in the trendy disco. Some of the people left and returned to attack the others.
State authorities said they are studying surveillance video from inside the nightclub to help determine what happened.
While there have been isolated grenade attacks around the city, Saturday's was the first to be thrown into a crowd and cause so many injuries.
The U.S. Consulate in Guadalajara recently warned U.S. citizens not to drive at night in parts of the city after suspected drug-gang members burned vehicles and blocked streets.
Such alerts have become common for highways in some areas of northern and western Mexico, but not for Guadalajara, which is known more for its mariachi music and tequila than as a focal point of a drug war that has claimed nearly 35,000 lives since 2006.
But in recent months the picturesque colonial city has come to resemble embattled areas of northern Mexico - including the state of Nuevo Leon, where Monterrey is located.
Seven presumed cartel gunmen were shot dead by soldiers near Monterrey during a chase and shootout just after midnight Friday. A civilian was also killed when the gunmen crashed into his car as they tried to flee soldiers.
A soldier and a state police officer were wounded during the clash in the suburban city of San Nicolas, the military said in a news release.
Soldiers also freed a woman who is presumed to have been kidnapped and was traveling in one of the vehicles. Two other vehicles, carrying an unknown number of attackers, escaped, and there were no arrests, said a spokesman for the state public security office, who was not authorized to give his name.
Nuevo Leon has been hit by a wave of drug-fueled violence in recent years as the Gulf Cartel battles a gang of its former enforcers known as the Zetas.
The cartels have staged a bloody turf war over drug peddling points and smuggling routes to the U.S. border 125 miles (200 kilometers) to the north, and clashes with the military and police have become almost a daily occurrence in and around Monterrey.
In Guadalajara, the violence has heated up just in the past few months from cartels warring for turf. The city is key to western drug routes once controlled by former Sinaloa leader Ignacio "Nacho" Coronel, who was killed in a gunbattle with soldiers in July.
Associated Press writer Mark Walsh in Monterrey, Mexico, contributed to this report.