Rafael Benitez's men travel to Slovakia having beaten Sparta Prague 3-1 in their Group A opener.
In contrast, Slovan were hammered 5-0 at Young Boys, but Hamsik is adamant that his former side will pose a stern test for Benitez's side.
He told Pravda.sk: "Slovan are one of the strongest and oldest clubs in Slovakia. They are not to be underestimated.
"They've had a difficult start to the league, but they're getting there. It's also important to differentiate between League and Cup, they’re different competitions."
Although he only made six appearances for Slovan before leaving for Brescia in 2004, the 27-year old is still highly revered by the club's fans.
And Hamsik, who could line up alongside Gonzalo Higuain, Lorenzo Insigne and Jonathan de Guzman, is looking forward to returning to the Stadion Pasienky.
"I'll be face to face with a club where I spent two beautiful years which opened the way to football on the international stage," he added
"It'll be an encounter that will have a special meaning for me. My parents and my closest friends will be at the stadium."
Benitez has come in for criticism this season since his side's early exit from the Champions League at the hands of Athletic Bilbao.
The former Liverpool boss is expected to chop and change for the tie.
He said: "Those who come in have to prove their level and their quality. Every game is one to win as far as we are concerned.
"It is always easier to win when you play well and that helps you to more victories.”
