Undefeated in 23 matches in all competitions since April`s Champions League semi-final against Atletico Madrid, Chelsea proved far from invincible as 10-man Newcastle survived a late barrage to secure a thrilling victory at St James` Park.
Few could deny Newcastle deserved it.
They lost goalkeeper Rob Elliot to injury at halftime, replaced by young rookie Jak Alnwick, and were reduced to 10 men when Steven Taylor was dismissed after getting a second yellow card 10 minutes from the end.
Substitute Cisse, who replaced Remy Cabella after the break, put Newcastle in front after 57 minutes following a slip by Gary Cahill and struck again on the break 20 minutes later, seconds after Eden Hazard was denied an equaliser by the woodwork.
Didier Drogba`s majestic header halved the deficit and there were groans from the home fans when six minutes of added time were indicated.
Newcastle rode their luck, however, and Chelsea`s 14-match unbeaten start to the season, which had drawn comparisons with the Arsenal side that went through the 2003-04 league campaign unbeaten, was over.
Champions Manchester City can close the gap at the top to three points if they beat Everton later on Saturday.
Chelsea, with Diego Costa back in attack after missing the midweek win over Tottenham Hotspur through suspension, dominated for long periods but were unusually profligate in front of goal.
Willian should have scored midway through the first half but shot narrowly wide and the Brazilian forced Elliot into a diving save. Costa also failed to capitalise from a couple of dangerous situations.
Elliot limped off at halftime and failed to reappear, allowing 21-year-old Alnwick to make his first competitive appearance.
However, it was Newcastle`s second substitution that proved the most telling as Cisse strode on.
The Senegal striker had barely touched the ball when Sammy Ameobi`s low cross was not cleared by Cahill and he had the simplest of tasks to tap the ball past Thibaut Courtois.
Chelsea responded with Hazard hitting the post but Newcastle went further ahead after a counter-attack ended with Moussa Sissoko setting up Cisse for another tap-in.
Taylor`s sending-off and Drogba`s second goal of the week silenced the home crowd but Mourinho was left still waiting for his first away league victory over Newcastle.