It was veteran Brit Hamilton's first victory since winning the Belgian Grand Prix in July 2024 while still with Mercedes, and it means the seven-time world champion has now boosted his record career haul to 106 GP victories.
Hamilton took his opportunity as runaway Italian title leader Kimi Antonelli - who had won five on the bounce coming into the race - suffered a late retirement due to engine failure, while George Russell, starting from pole, finished second.
Piastri's McLaren team-mate and defending F1 champion Lando Norris finished third ahead of four-time champ Max Verstappen (Red Bull).
Australian star Piastri, who won in Barcelona last year, had earlier seen his hopes of a much-needed pole position sunk in the final stages of qualifying.
Despite Piastri being placed quickest after two laps of Q3, Charles Leclerc slipped off the gravel on turn 4, allowing Russell, Hamilton and Antonelli to take advantage after a restart to move ahead of him for the starting grid.
Piastri's fifth place in Spain earned him 10 points to leave him sixth overall in the drivers championship.
"A tricky day for us. We just struggled with grip and pace throughout the race, so we weren't able to make any progress," Piastri admitted afterwards.
"The conditions today were also very different to Friday, where we felt a bit stronger. We need to do some work to understand why we found it so difficult.
Hamilton, who has finally won his first race since joining Ferrari two years ago, was emotional after ended a streak of 40 races without topping the podium.
"They are all special in their own way, but this one is something else," Hamilton said trackside.
"I watched Ferrari have all this success when I was younger and wondered what it would be like to win in this car. And now it has come true."
