The 40-year-old started on the bench on Saturday night, much to the anger of the home support, but was introduced on 52 minutes to an incredible ovation.
Since arriving at the club back in 1995, Zanetti has gone on to become the most decorated player in the club's history, lifting 16 trophies over the course of his time in Italy.
At full-time on Saturday the Inter staff gave a visibly-emotional Zanetti a guard of honour, before the Argentine took the microphone and said his thanks.
"Thank you everyone," he began. "You've no idea how emotional this moment is. To say you are all fantastic is not enough.
"I want to thank everyone who has been close to me at any moment. I want to thank my wife Paula and the wonderful family we raised together.
"My father, who is in front of the television in Argentina right now and didn't want to come here. I thank my mother in the heavens, who is certainly as happy as I am right now. I thank the Moratti family, who in all these years have shown faith in me.
"I thank President Thohir, who allows me to continue in this wonderful Inter family, which was always my dream. I thank my fantastic team-mates, those of this season and every year before that, who showed me so much respect and affection."
Zanetti will now become the club's sporting director and said he will continue to be as dedicated off the pitch as he has been on it over the past two decades.
"I am happy for this wonderful career wearing this jersey which I truly love," he added. "Now I must do something else.
"I don't know if I will do it well, but I can say that I will defend Inter the way I defended it on the field.
"My only desire was to defend and honour the Inter jersey in any country all over the world. I learned to love it thanks to you. I ask you to love this club, just as I will love it forever.
"Thank you for having loved me. I truly love you."