It happened around 9:45 p.m. on the 3600 block of Germantown Avenue near Max's Steaks in the city's Tioga-Nicetown section.
Police tell Action News that the shooting critically injured a 34-year-old man and an unidentified male victim.
Two others, an 18-year-old woman and a 33-year-old man, are listed in stable condition after being shot, said police.
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Chopper 6 was overhead as officers cordoned off an area near the busy intersection of Erie and Germantown avenues.
It's still unclear what led up to the gunfire.
No arrests have been made.
Anyone with any information is asked to call police at 215-686-TIPS.