Salmonella typhimurium is a facultative anaerobic bacterium able to multiply preferentially in tumors and inhibit their growth. The mechanisms through which Salmonella exerts its anti‐cancer properties are not fully understood. We recently showed that intra‐tumoral Salmonella injection results not only in the regression of even bulky tumor masses, but also impacts on the growth of distant untreated lesions. Here we describe how Salmonella exerts its systemic anti‐cancer effects and means to potentiate them. The outburst of an early inflammatory reaction in the treated tumor promotes the development of an immunostimulatory cytokine environment both locally and in the draining lymph node. Within the next 10 days, an efficient cross‐presentation of endogenous tumor antigens by dendritic cells at the tumor‐draining lymph node leads to the priming of effective anti‐tumor CD8⁺ T cell responses. This potentially broadly reactive T cell repertoire can be directed to other pre‐established melanomas by low‐dose radiotherapy enhancing the Salmonella anti‐cancer effect. We demonstrate that Salmonella‐based therapy coupled to low‐dose radiotherapy dampens tumor immune escape mechanisms at different levels and allows controlling systemic disease in a CD8⁺ T cell‐dependent manner.