"As we look forward to the mid-term elections this November, Democrats nationwide should be on notice: Americans are ready to hold the party in power accountable for their irresponsible spending and out-of-touch agenda, and they're ready for real change in Washington," National Republican Campaign Committee chairman John Cornyn said after Brown's victory.
Massachusetts, where registered Democrats outnumber Republicans by more than three to one, has long been a Democratic stronghold, sending two Democratic senators to Washington for each of the past 31 years.
The last time a Republican senator was elected in Massachusetts was November 1972, when Sen. Edward Brooke won the coveted seat.
Sen. Robert Menendez, D-N.J., the chairman of the Democratic Senate Campaign Committee, said the message voters sent in Brown's victory was not lost on the party.
"I have no interest in sugar coating what happened in Massachusetts," Menendez said. "There is a lot of anxiety in the country right now. Americans are understandably impatient. The truth is Democrats understand the economic anger voters feel, that's in large part why we did well in 2006 and 2008.
"In the days ahead, we will sort through the lessons of Massachusetts: the need to redouble our efforts on the economy, the need to show that our commitment to real change is as powerful as it was in 2008, and the reality that we cannot take a single thing for granted and cannot afford even a second of complacency."
ABC News' Dean Norland and Z. Byron Wolf contributed to this report.