As often seen this season, pole-sitter Sykes made a flying start ahead of Davide Guigliano while Max Biaggi on his WSBK return spiced up the action as he fought tooth and nail including a near-miss with Rea and a light touch with Sylvain Guintoli.
Sykes almost immediately began to put some clean air between himself and Giugliano while Leon Haslam and Rea fought over third place. There was disappointment for Jordi Torres who crashed out of fifth place, which elevated Chaz Davies and Biaggi up the order.
The two-rider battle for third became a four-way tussle as Davies caught Haslam, making short work of taking fourth off the Aprilia rider, who then came under attack from his new team-mate, Biaggi.
While that quartet traded blows, Sykes took advantage, picking up the pace to etch out a lead of 1.7s over Giugliano at the midway stage of the 21-lap Misano race. The 2013 WSBK Champion appeared to have broken the challenge of the Dutaci rider as a lap later the gap was up to 2.1s and then 2.5.
Giugliano's second was also under threat as Rea and Davies, despite trading blows, were notably quicker and started to close up. They in turn had dropped Haslam and Biaggi who were comfortably ahead of Guintoli, who was battling Ayrton Badovini and Michael van der Mark.
With three to go Giugliano dropped from second off the podium as he was overtaken by Rea, who had dived up the inside of Davies and then Giugliano, and then by Davies. The duo immediately dropped the Italian, racing their way to the podium.
As the chequered flag waved, Sykes raced to only his third win of this season, 4.2s up on the chasing pack. The 25 points for the win elevated the Kawasaki rider to 231 points.
Rea finished second, minimising the damage Sykes' win caused to his Championship lead, while Davies, despite a late move which ended when he ran wide, completed the podium in third place.
Giugliano was a disappointing fourth ahead of Haslam, Biaggi, Badovini and Michele Pirro.
1 SYKES Tom Kawasaki ZX-10
2 REA Jonathan Kawasaki ZX-10R 3.613
3 DAVIES Chaz Ducati Panigale R 4.178
4 GIUGLIANO Davide Ducati Panigale R 5.944
5 HASLAM Leon Aprilia RSV4 RF 12.155
6 BIAGGI Max Aprilia RSV4 RF 12.352
7 BADOVINI Ayrton BMW S1000 RR 18.145
8 PIRRO Michele Ducati Panigale R 18.328
9 GUINTOLI Sylvain Honda CBR1000RR SP 20.088
10 VD MARK Michael Honda CBR1000RR SP 20.282
11 MERCADO Leandro Ducati Panigale R 24.195
12 LOWES Alex Suzuki GSX-R1000 26.625
13 CAMIER Leon MV Agusta F4 RR 26.719
14 RAMOS Román Kawasaki ZX-10R 31.898
15 BAIOCCO Matteo Ducati Panigale R 32.643
16 REITERBERGER Markus BMW S1000 RR 36.833
17 SALOM David Kawasaki ZX-10R 42.514
18 PONSSON Christophe Kawasaki ZX-10R 70.247
19 BARRAGÁN Santiago Kawasaki ZX-10R 70.536
20 VIZZIELLO Gianluca Kawasaki ZX-10R 88.191
21 RIZMAYER Gábor BMW S1000 RR 98.856
22 TOTH Imre BMW S1000 RR 1 LAP
Did Not Finish
CANEPA Niccolò Ducati Panigale R 6 LAPS
DE PUNIET Randy Suzuki GSX-R1000 10 LAPS
TORRES Jordi Aprilia RSV4 RF 18 LAPS