Both Inter and Lazio went into the encounter needing points in their respective bids for European qualification, but all eyes were on Zanetti, the most decorated player in Inter's history.
Forty-year-old Zanetti, who is also Argentina's most-capped player with 145 outings, has claimed 16 trophies with Inter since signing from Banfield in 1995, but his 857th showing for the Milan giants had to wait until after half-time.
At first the hosts appeared to be in for a long day as Giuseppe Biava put Lazio into the lead after just two minutes, but the hosts fought back and ended up going into the break with a 3-1 lead thanks to two goals from Rodrigo Palacio and Mauro Icardi's strike.
Zanetti was introduced to a magnificent reception just after half-time and although the visitors created several excellent chances in the second period, Hernanes ended his former team's slender hopes of a late comeback with a stunning effort from range.
Triumph means Inter are almost guaranteed a place in the UEFA Europa League, with defeat for Lazio ending their hopes of a top-six finish.
Verona's own bid for a Europa League place took a major blow after they surrendered a two-goal lead at home to Udinese in Saturday's earlier match.
Luca Toni netted his 20th Serie A goal of the season from the penalty spot in the 14th minute, getting the hosts off to a great start at Stadio Marc'Antonio Bentegodi.
The hosts doubled their lead through Emil Halfredsson eight minutes into the second period, but Antonio Di Natale's wonder strike just two minutes after proved to be Udinese's inspiration.
The Italian forward produced an exquisite touch to bring down a cross, before swivelling and belting an emphatic volley into the roof of the net.
Emmanuel Agyemang-Badu scored the equaliser in second-half stoppage time and although the point does little for 13th-placed Udinese, Verona now require a draw between Torino and Parma on Sunday to keep their top-six hopes alive.
