Jonny Williams put Wales 1-0 up in the 52nd minute of the game at the Municipal Stadium in the southwestern Polish city of Wrocław.
Poland's Jakub Kamiński produced an equalizer 20 minutes later.
Karol Świderski found the back of the net from close range in the 85th minute, clinching the winner for Poland.
Poland, captained by star striker Robert Lewandowski, were looking to put up a strong performance in their Nations League opener as they start a series of matches against higher-ranked European teams in the run-up to the World Cup in Qatar.
Poland, captained by star striker Robert Lewandowski, beat Wales 2-1 at home on Wednesday in their first match in the group stage of the 2022/2023 UEFA Nations League. Photo: PAP/Maciej Kulczyński
Poland are ranked 26th worldwide by football's governing body FIFA, while Wales are No. 18 in the FIFA table.
The Polish team next takes on Belgium in Brussels on June 8 and the Netherlands in Rotterdam on June 11 in the Nations League.
On June 14, Poland will face off against Belgium on home turf in Warsaw.
The Nations League is the European football governing body UEFA’s newest national-team competition that is now in its third edition.
The competition is designed to enable teams to play against those that are similarly ranked and may also offer an alternative path for teams to qualify for the 2024 European championships.
Portugal won the first edition of the Nations League in 2019, while France won the 2020/2021 UEFA Nations League after beating Spain 2-1 in the final in Milan in October.
The 2022 World Cup, meanwhile, will be held in Qatar from November 21 to December 18.
Poland have been drawn to play Argentina, Mexico and Saudi Arabia in the group stage of the tournament.
The Polish team qualified for the World Cup after defeating Sweden 2-0 in a playoff at home in late March.
Source: TVP Sport, PAP