In parallel, Megrelishvili founded the Patients' Rights Union, a non-governmental organization focused on health care, leading it for three years before being appointed as Deputy General Director of the Social Insurance Fund of Georgia.

In 2004, Vakhtang Megrelishvili was appointed as Deputy Minister of Labor, Health and Social Protection in the new government created after the Rose Revolution, serving under the ministership of Vladimer Chipashvili.

[6] In July 2018, he filed with Zurab Japaridze a lawsuit against Article 45 of Georgia's Administrative Code which outlined financial sanction guidelines for the recreational use of marijuana, arguing its incompatibility with the Constitution.

[11] Along with the rest of the opposition, Megrelishvili declared a parliamentary boycott and refused to accept his seat after allegations of large-scale voter fraud surfaced, though he was one of the few MPs to not file for resignation.

During inter-party opposition negotiations, he abruptly left the meeting alongside Iago Khvichia following disagreements over the anti-governmental forces' protest strategy.

[17] On April 19, 2021, he was one of the signatories of the Orbeliani Palace Agreement, a compromise negotiated by Charles Michel and saw part of the opposition agreeing to end the boycott in exchange of a series of judicial and electoral reforms.

In a joint statement with five other MPs published in August 2022, he called for the implementation of the 2021 agreement, the abolition of the 5% electoral threshold for parliamentary parties, the transfer of imprisoned Mikheil Saakashvili abroad, and the return of Bidzina Ivanishvili to Georgian politics.

Himself a former professor and founder of a private school, he has regularly criticized the public education system of Georgia, calling it "beyond reform or improvement", and "based on violence and propaganda".

[25] His statements were criticized by the Partnership for Human Rights, who asked the Parliamentary Ethics Council to study them, as well as by Public Defender Nino Lomjaria.

He is one of the founders of the so-called Church of Biblical Freedom, an pseudo-religious organization created by Girchi activists to help young men avoid military service by granting them the status of "priest".

During the 2022 Russian invasion of Ukraine, he backed the proposal of Georgia joining international sanctions and criticized the Georgian government for refusing to do so, comparing the Irakli Gharibashvili administration's decision to Belarus's alliance with Russia.

[29] He has also been critical of the Georgian government's rhetoric against European Union member states and has instead favored exchanging reform ideas with Ukraine on both countries' EU integration paths.