In 2004, Cornyn co-founded and became the co-chairman of the U.S. Senate India Caucus.
In December 2006, he was selected by his colleagues to join the five-person Republican Senate leadership team as Vice Chairman of the Senate Republican Conference.

In 2005, Cornyn gained notice by connecting the Supreme Court's reluctance to hear arguments for sustaining Terri Schiavo's life with the recent murders of Judge Joan Lefkow's husband and mother as well as the courtroom murder of Judge Rowland Barnes.
Cornyn said: "I don't know if there is a cause-and-effect connection, but we have seen some recent episodes of courthouse violence in this country.
I wonder whether there may be some connection between the perception in some quarters on some occasions where judges are making political decisions yet are unaccountable to the public, that it builds up and builds up and building up to the point where some people engage in violence".
His statement and a similar one by House Majority Leader Tom DeLay were widely denounced, including by The New York Times.
Cornyn later said that the statement was taken out of context and for that reason he regretted the statement.

On May 18, 2007, Cornyn was involved in an altercation with the late Senator John McCain.
During a meeting on immigration, McCain and Cornyn had a shouting match when Cornyn started questioning the number of judicial appeals that illegal immigrants could receive.
McCain yelled an insult at Cornyn and said "I know more about this than anyone else in the room."
Previously, Cornyn told McCain, "Wait a second here.
I've been sitting in here for all of these negotiations and you just parachute in here on the last day.
You're out of line."

As chairman of the National Republican Senatorial Committee, Cornyn was a strong supporter of Norm Coleman's various court challenges to the 2008 election certification of the Minnesota U.S. Senate race.
Cornyn advocated for Coleman to bring the case before the federal court, and said the trial and appeals could take years to complete.
Cornyn threatened that Republicans would wage a "World War III" if Senate Democrats had attempted to seat Democratic candidate Al Franken before the appeals were complete.
Coleman conceded after the Minnesota Supreme Court unanimously ruled that Franken had won the election.

On the day of Obama's inauguration, it was reported that Cornyn would prevent Hillary Clinton from being confirmed as secretary of state by unanimous floor vote that day.
Senate Majority Leader Harry Reid's spokesman reported to the Associated Press that a roll call vote for the Clinton confirmation would be held instead on the following day, January 21, 2009, and that it was expected Clinton would "receive overwhelming bipartisan support".
The vote was 94–2 in her favor, with only Senators Jim DeMint (R-SC) and David Vitter (R-LA) voting in opposition.

On March 18, 2020, Cornyn blamed the COVID-19 pandemic on cultural practices in China and mistakenly blamed China for the MERS and swine flu epidemics.
His comments were criticized by some Democrats and the National Council of Asian Americans and Pacific Islanders.
At the time, the consensus among researchers was that coronavirus had originated at a wet market in Wuhan, China.
In 2004, Cornyn co-founded and became the co-chairman of the U.S. Senate India Caucus. In December 2006, he was selected by his colleagues to join the five-person Republican Senate leadership team as Vice Chairman of the Senate Republican Conference.
In 2005, Cornyn gained notice by connecting the Supreme Court's reluctance to hear arguments for sustaining Terri Schiavo's life with the recent murders of Judge Joan Lefkow's husband and mother as well as the courtroom murder of Judge Rowland Barnes. Cornyn said: "I don't know if there is a cause-and-effect connection, but we have seen some recent episodes of courthouse violence in this country. I wonder whether there may be some connection between the perception in some quarters on some occasions where judges are making political decisions yet are unaccountable to the public, that it builds up and builds up and building up to the point where some people engage in violence". His statement and a similar one by House Majority Leader Tom DeLay were widely denounced, including by The New York Times. Cornyn later said that the statement was taken out of context and for that reason he regretted the statement.
On May 18, 2007, Cornyn was involved in an altercation with the late Senator John McCain. During a meeting on immigration, McCain and Cornyn had a shouting match when Cornyn started questioning the number of judicial appeals that illegal immigrants could receive. McCain yelled an insult at Cornyn and said "I know more about this than anyone else in the room." Previously, Cornyn told McCain, "Wait a second here. I've been sitting in here for all of these negotiations and you just parachute in here on the last day. You're out of line."
As chairman of the National Republican Senatorial Committee, Cornyn was a strong supporter of Norm Coleman's various court challenges to the 2008 election certification of the Minnesota U.S. Senate race. Cornyn advocated for Coleman to bring the case before the federal court, and said the trial and appeals could take years to complete. Cornyn threatened that Republicans would wage a "World War III" if Senate Democrats had attempted to seat Democratic candidate Al Franken before the appeals were complete. Coleman conceded after the Minnesota Supreme Court unanimously ruled that Franken had won the election.
On the day of Obama's inauguration, it was reported that Cornyn would prevent Hillary Clinton from being confirmed as secretary of state by unanimous floor vote that day. Senate Majority Leader Harry Reid's spokesman reported to the Associated Press that a roll call vote for the Clinton confirmation would be held instead on the following day, January 21, 2009, and that it was expected Clinton would "receive overwhelming bipartisan support". The vote was 94–2 in her favor, with only Senators Jim DeMint (R-SC) and David Vitter (R-LA) voting in opposition.
On March 18, 2020, Cornyn blamed the COVID-19 pandemic on cultural practices in China and mistakenly blamed China for the MERS and swine flu epidemics. His comments were criticized by some Democrats and the National Council of Asian Americans and Pacific Islanders. At the time, the consensus among researchers was that coronavirus had originated at a wet market in Wuhan, China.
John Cornyn