The Finnish former Liverpool defender took over at the Championship from the departing Oscar Garcia in June, but leaves with Brighton languishing in the bottom three.
Despite a run of one win in 18 league matches, chairman Tony Bloom admitted he was reluctant to allow Hyypia to leave.
"Sami offered his resignation, and we reluctantly accepted earlier today," he said. "Sami has worked extremely hard since joining the club last summer.
"Despite some good performances, including most recently at Wolves (1-1), results haven't gone as well as we all had hoped and expected.
"Sami is an incredibly honourable man. He remains a hugely respected and very popular figure at our club. He has decided to step down for the benefit of the team and the club.
"We are all very disappointed, but we respect Sami’s decision and we all wish him well for the future."
Brighton have reached the play-offs in the past two seasons.
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