(1) Background: Well-known monosodium glutamate (E-621, MSG), originally used as a food flavor enhancer, was approved approximately in all countries, but the toxicity versus the safety of (MSG) are still unclear due to variable scientific toxicological reports. Moreover, it was reported to trigger elevated frequencies of nausea and headaches in humans and provide deleterious effects on laboratory animals. The objectives of the present study were to (i) estimate the possible toxic effects of the food additive MSG (ii) and the ameliorating protective effects of the dietary supplement spirulina (Spirulina platensis) on the biochemical parameters of blood and the damage produced in organs of Swiss mice after applying a supplementary daily dose of MSG for 4 weeks. (2) Methods: The present study was conducted on 20 mature Swiss mice, which were randomly organized into four groups of five Swiss mice. The treatments were (I) the control group, in which Swiss mice were fed only animal feed and drinking water; group II MSG1, which received 1 mL of MSG; group III MSG0.5, which was treated with 0.5 mL of MSG; and (IV) the group MSGS, which was treated with 1 mL of monosodium glutamate and 1 mL of spirulina (aiming to reduce the MSG toxicity). (3) Results: At the end of the experiment, Swiss mice treated with MSG demonstrated a passiveness regarding behavioral aspects. As we hypothesized, the parameters of the spirulina group reached similar values to the control group, and no histopathological observations have been found. Altogether, our findings evidenced that monosodium glutamate leads to histopathological changes in Swiss mice kidneys and caused important modifications for all biochemical parameters of the blood serum. Noticeably, the potential protective effect of Spirulina platensis was proved and was described by using the FTIR spectroscopy technique. (4) Conclusions: A diet rich in antioxidants and other plant-derived bioactive compounds may provide healthy nutrition, alleviating the potential side effects of some food additives.