The 38-year-old Lewandowski scored once from the penalty spot in the first half and twice after the break to take his international tally to 92 goals. It was his seventh hat-trick for Poland.
Despite the impressive victory, Poland remain in third place in their Nations League group with four points from three games.
Sweden lead Group B4 with seven points after drawing 1-1 with Bosnia and Herzegovina, who have five. Romania have lost all three of their games.
Poland had one point from their first two games, drawing 0-0 with Bosnia and Herzegovina and losing 1-3 to Sweden. Romania had lost to Sweden 1-2 and Bosnia 2-4.
The Polish and Romanian teams were meeting for the first time in nine years. Poland took both games against Romania in qualifying for the 2018 World Cup in Russia, winning 3-0 in Bucharest and 3-1 in Warsaw.
Poland captain Lewandowski returned to the starting lineup for his 170th international appearance, partnering Karol Świderski in attack.
Inter Milan midfielder Piotr Zieliński made his 112th appearance for Poland, while 22-year-old Wiktor Nowak made his third appearance for the senior national team.
Poland took the lead in the 22nd minute after Radu Drăgușin fouled Lewandowski in the penalty area. Drăgușin was sent off and Lewandowski converted the penalty for his 90th international goal.
Poland led only 1-0 at halftime despite playing against 10 men.
The hosts quickly pulled away after the break. In the 47th minute, Nicola Zalewski broke down the left and set up Lewandowski for his second goal.
Two minutes later, a shot by Przemysław Frankowski deflected off Romania defender Virgil Ghiță and into the net for an own goal.
Zieliński made it 4-0 in the 62nd minute after Romanian midfielder Răzvan Marin's attempted back pass fell to him. He lobbed the goalkeeper and scored.
Jan Bednarek headed in Poland's fifth goal after Sebastian Szymański's corner.
Lewandowski completed his hat-trick in the 86th minute, dribbling past several defenders inside the penalty area before finding the net.
It was Poland's biggest victory since September 5, 2021, when they beat San Marino 7-1 in World Cup qualifying under then-coach Paulo Sousa, state news agency PAP reported.
'I felt my strength coming back': Lewandowski
Lewandowski said he felt much stronger against Romania than in Poland's previous games against Bosnia and Sweden.
"I felt my strength coming back," Lewandowski told broadcaster TVP Sport.
The Chicago Fire forward joined the national team after flying in from the United States and said he struggled with jet lag in the first few days.
"In the first game, my legs felt like cotton. It was difficult," he said. "It was my first trip like that, and at this age it's not so easy to prepare properly."
Lewandowski said he was pleased both with his hat-trick and Poland's emphatic victory.
The striker, however, will miss Monday's game against Bosnia and Herzegovina in Zenica after receiving his second yellow card of the Nations League campaign. His first came in the defeat to Sweden.
Lewandowski said he was disappointed to miss the game after scoring three goals but expressed confidence in his teammates.
"We have a strong enough team that there are other players who will certainly replace me well," he said.
Poland's final two Nations League matches are scheduled for next month, away to Romania on November 14 and at home against Sweden in Wrocław three days later.
Poland were relegated from Division A under former coach Michał Probierz in the autumn of 2024 after finishing last in a group containing Portugal, Croatia and Scotland.
Scotland also went down after losing in the relegation playoffs.
Poland are now seeking a return to the top division. The winner of their Division B group will earn direct promotion, while the runner-up will have a chance to advance through a playoff.
The third-place team will enter a playoff to avoid relegation, while the fourth-place team will drop to Division C.
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Source: TVP Sport, IAR/PAP