Mertens scored his 121st goal for Napoli in all competitions as the Italian side drew 1-1 with LaLiga champion Barca in the first leg of their last-16 tie.
The 32 year-old forward matched the record with a stunning 30th-minute opener at Stadio San Paolo, where Barca salvaged a draw thanks to Antoine Griezmann.
Mertens, who leapfrogged Diego Maradona (115) into second place on the all-time list in October, was substituted in the 54th minute at home to Lionel Messi's Barcelona.
Afterwards, Napoli released a statement which read: "Dries Mertens sustained bruising to his right ankle during a collision which forced him to leave the pitch early in the second half of tonight's match against Barcelona."
Mertens joined Serie A side Napoli from PSV in 2013 and the Belgium international has flourished.
Of Mertens' 121 goals, 90 have come in Serie A, with another 26 via European competition.
This season Mertens – who is out of contract at the end of the season amid links to the likes of Inter and Chelsea – has scored 12 goals across all competitions for Napoli.