Inter's Rodrigo Palacio struck either side of a neat first-time finish from Mauro Icardi in the first half beofre a powerful long-range strike from ex-Lazio midfielder Hernanes 11 minutes from time gave the hosts an impressive victory.
Lazio had taken the lead in the second minute with Giuseppe Biava's tap-in but that was as good as it got for the visitors.
The loudest cheer of the night was reserved for 40-year-old Zanetti, who was introduced as a 52nd minute substitute to make his 614th Serie A appearance for Inter.
He was applauded by a San Siro crowd missing the ultra fans from the Curva Nord, which has been closed for three matches following offensive chanting during last month's goalless draw with Napoli and a 1-0 defeat in the Milan derby last weekend.
In added time an Inter supporter wearing a replica shirt with "ZANETTI" on the back got on to the pitch and had to be escorted away by the defender, who spoke to the fan and was given a standing ovation by the whole ground as he did so.
Walter Mazzarri's Inter side stay fifth after the win but are now only a point behind Fiorentina, who play in a Tuscan derby at bottom side Livorno on Sunday, and are guaranteed a spot in next season's Europa League.
Inter are also six points ahead of local rivals AC Milan, who visit Atalanta on Sunday, Parma and Hellas Verona, who lost a two-goal lead to draw 2-2 with Udinese after veteran striker Luca Toni scored his 20th goal of the season with the 14th minute opener from the penalty spot.
With two games left that trio are a point behind Torino, who occupy the last Europa League place and host Parma on Sunday. The defeat leaves Lazio in 10th place two points behind Torino but they could still qualify for Europe.
- Sports & Recreation
- Mauro Icardi