Her decision comes after a cabinet reshuffle last week forced by former education minister Sarah Courtney's move to quit politics amid criticism of her overseas holiday during back-to-school preparations.
Premier Peter Gutwein indicated Ms Howlett would remain in parliament as an upper house member.
"This has been a very difficult decision for Jane. However, I support and respect her decision to prioritise the wellbeing of her family," Mr Gutwein said on Friday.
Ms Howlett, who was elected to the Legislative Council in 2018 in the southeast seat of Prosser, was minister for racing, women, small business, hospitality and events, and disability services.
Mr Gutwein indicated he was likely to hand the portfolios to one of several Liberal lower house or upper house members, avoiding substantial cabinet movement before parliament resumes next week.
Mr Gutwein said Ms Howlett's brother died on the morning the new cabinet was sworn in.
"(Politics) is the one business that people, regardless of personal circumstances, regardless of what's occurring outside of their job ... are expected to stand up and just get on with it," he said.
"To actually do what she did last week and carry on with her ministerial duties in the following days was just extraordinarily brave.
"But we're human beings. When Jane spoke to me (on Thursday) she said that she needed to have a break."
Ms Courtney quit politics on February 10, citing a desire to spend more time with family, after returning from France where she had caught COVID-19.Â
State Labor Opposition Leader Rebecca White said the government was in chaos and there were slim pickings to replace Ms Howlett.
Ms Howlett, who did not appear alongside Mr Gutwein at the press conference announcing her standing down, is expected to take several weeks off work.
"This was an incredibly difficult decision to make, but the correct one for my family and myself," she said in a statement.
"Above all, I would like to thank my family for their support. This has been a very challenging time and now it is time for me to return that support to them."
The ministerial departures come less than a year after the Liberals were re-elected for a record third successive term.
Mr Gutwein will manage Ms Howlett's portfolios until they are reassigned. She also held the sport portfolio until the most recent reshuffle.
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