After his unlikely victory in Azerbaijan, it was a second straight win for Hamilton as he bids for a fifth world championship -- and it could not have been more comfortable.
His teammate Valtteri Bottas finished over 20 seconds behind with Red Bull's Max Verstappen completing the podium.
Hamilton's nearest title challenger, Ferrari's Sebastian Vettel, finished a disappointing fourth, handicapped by a slow second pit stop which ultimately cost him valuable points.
To complete a sorry afternoon for Ferrari, his teammate Kimi Raikkonen was forced to retire, leaving Mercedes to take the lead in the constructors' championship with a 27-point advantage.
Hamilton led from pole, with Vettel nipping ahead of Bottas to initially take second, but behind them there was carnage as Romain Grosjean span his Haas, with the luckless Nico Hulkenberg (Renault) and Pierre Gasly (Toro Rosso) ploughing into him.
While the three cars were cleared from the track a safety car was deployed, but once it moved aside Hamilton powered clear of his closest rivals.
"I felt a synergy with the car that I hadn't been feeling all year," said the Briton who was claiming his 64th career victory and third in Spain at the Circuit de Catalunya.
Vettel came in for the second stop under Virtual Safety Car (VSC) conditions when Esteban Ocon's Force India stopped on the track.
It looked a tactical error by Ferrari, but the German said the tires on his car were wearing faster than that of his closest rivals and he could not close the gap fast enough on Verstappen, who had stayed out.
This despite the young Dutchman making an error during the VSC as he touched the back of the Williams of Lance Stroll, losing part of his front wing in the process.
Australian Daniel Ricciardo was fifth in the second Red Bull ahead of Dane Kevin Magnussen in his Haas.
Spaniards Carlos Sainz, of Renault, and two-time champion Fernando Alonso for McLaren finished seventh and eighth.
Mexican Sergio Perez of Force India made a late overtaking move on Sauber's Charles Leclerc for ninth, but it had been another impressive performance by the young Monegasque, who was involved in a great early battle with home hero Alonso.
Hamilton will go to the next round in the iconic venue of Monte Carlo with a spring in his step after an imperious drive, registering several lap records as he built his winning lead.
"That's more like it guys, great job," he told his team at race finish, having previously vented his frustrations after a slow start to the season with arch-rival Vettel leading up until the previous round in Baku.