[2] Pupatello made an unsuccessful attempt at returning to elected office in 2019 when she stood as the federal Liberal candidate in Windsor West.

The Progressive Conservative Party won a majority government in the election, and Pupatello entered the legislature as an opposition Member of Provincial Parliament (MPP).

[13] She later criticized the Progressive Conservative government's plans to introduce a private MRI clinic, arguing that it posed a long-term threat to public health care.

[16] Pupatello's most important responsibility in the Community and Social Services portfolio was overseeing Ontario's welfare and disability assistance system.

Shortly after taking office, she announced that her government would remove a lifetime ban on welfare recipients who are caught cheating on their applications.

Pupatello described the rule as counterproductive, in that many welfare officials were reluctant to bring forward charges out of concern for the extreme punitive consequences.

Ontario Privacy Commissioner Ann Cavoukian was a critic of the bill, arguing that it was not sufficiently respectful of the promises of anonymity made to birth parents at the time of adoption.

Groups such as the Ontario Coalition Against Poverty had previously encouraged recipients to apply for the benefit and there had been a significant increase in the number of requests.

Pupatello announced in January 2006 that her department would close Ontario's three remaining government-operated institutions for mentally disabled adults, and assist the occupants with moving into more integrated community facilities.

She noted that a "sea change in attitude" had occurred over institutionalization practices since the buildings were first established and that greater integration was now the preferred approach.

[31] She was unable to implement a planned removal of the federal tax credit clawback and argued that the deficit inherited from the previous government made this change unviable before 2007.

[33] She also pledged more than $1 million to provide young students with swimming and water survival lessons, in the aftermath of a series of drowning deaths in the Guelph area the previous year.

[34] In late May 2006, Pupatello introduced a strategic high school transition plan intended to reduce Ontario's high-school dropout rate.

[37] Pupatello also announced a comprehensive plan for changes at TV Ontario, including a greater focus on educational programming and more money for equipment upgrades.

[41] During a September 2006 by-election Parkdale—High Park, Pupatello engaged in a controversial negative campaign on behalf of Liberal candidate Sylvia Watson.

[42] Many argued that Pupatello took DiNovo's words completely out of context, and opposition politicians accused the Liberals of conducting a smear campaign.

Pupatello has defended her role in the campaign, saying "If I was presented once again with apparently what is factual and has yet to be refuted and that is sermons that were posted on the world wide web ...

[45] Pupatello led provincial trade delegations to Alberta in late 2006 and early 2007, promoting Ontario's business sector to the western province's booming economy.

[58] She lost to Kathleen Wynne who subsequently asked her to become Minister of Finance in her first cabinet; Pupatello declined in favour of returning to the private sector.

[1] She resigned in July 2015, despite having two years left in her contract,[62] after months of criticism from some Windsor city councillors who grilled Pupatello over the WEEDC's failure to create jobs in the region.

[68][69] In July 2021, Pupatello announced her intention to stand for the second time as the Liberal candidate for Windsor West in the 2021 Canadian federal election.

The expenditure figures cited on this page for all elections after 1995 are the Total Candidate's Campaign Expenses Subject to Limitation, and include transfers from constituency associations.