Ms Homer's departure after four years in charge of the UK tax office comes just weeks after she was awarded a damehood in the New Year's honours.
But under her leadership, HMRC has been criticised by MPs for "unacceptable" customer service and "disappointing progress" on tax evasion.
She will take a break over the summer after 36 years as a civil servant.
Her damehood aroused controversy among MPs, who argued her record in charge of HMRC and before that, the UK Border Agency, did not merit such recognition.
Ms Homer said she felt it was "a sensible time to move on" as HMRC had started to implement the government's latest spending plans.
"It has been a privilege to have been with HMRC during a period when the improved performance of the department has been increasingly recognised and we have the full backing of ministers for our future plans," she said in the announcement.
Chancellor George Osborne said Ms Homer had put foundations in place to make HMRC one of the most digitally-advanced tax authorities in the world.
"It is to Lin's great credit that the National Audit Office last year judged HMRC to be one of the strongest departments in government - a legacy of which she can be rightly proud," Mr Osborne said.
But in November, MPs on the public accounts committee issued a critical report, arguing HMRC must do more to ensure all tax is paid.
"It beggars belief that, having made disappointing progress on tax evasion and avoidance, the taxman also seems incapable of running a satisfactory service for people trying to pay their fair share," committee chair Meg Hillier said.
HMRC's customer service was considered "so bad" it could be leading to lower tax collection, the committee said.
The government has started the process to find Ms Homer's successor.
She is not "actively seeking" her next role, the government said.
HMRC chief executive Lin Homer, who faced criticism from MPs, will step down in April, the government has said.