Darwin's Sandwich Evolution, in Shoplatch, was targeted late on Sunday night. Police have been on the scene this morning with forensics to try to gather evidence, but the cafe has lost a day's trade and will be counting the cost of a smashed window and the loss of money.
It comes after a spate of break-ins around the town centre, as well as Shoplatch being a particular hotspot for violence and anti-social behaviour.
Owner Gwen Burgess said: "We thought it was settling down but it looks like we were wrong. They took all the money from the till, which unfortunately there was more than normal because I had a cash bill to pay.
"We think it happened at around 11.30pm to midnight. The guy at the Hole In The Wall said he heard something going on. Ashley's has CCTV and the university halls are checking theirs. It looks like it was five or six white males."
She added: "We still have the ongoing issues outside the shop.
"It's the last thing we want. It's been such a hard year for businesses. We're going to lose a day's trade. We want people to please come and support us."
Several break-ins were reported over the Easter Bank Holiday and the following weekend. Officers made arrests after £20,000 of watches were stolen from Goldsmiths of Shrewsbury. Other premises to be targeted have included Stop. Cafe in St Julian's Friars, The Allotment in Greyfriars Bridge, Strands hairdressers in Grope Lane and Nomad Coffee Co in Wyle Cop.
Police have increased patrols in the town, particularly in the Quarry, where there are also new security guards.