Nickel (Ni) and manganese (Mn) are well known for the production of steel and alloys and are commonly found co-occurring in Ni ores. They are metals of environmental concern and contamination in the marine environment is problematic single exposures and in combination. Several studies have documented the effects of single metal exposure on the model anemone E. pallida, but research on the effects of metal mixtures is far less common. This novel study assesses the accumulation and stress effects of Ni and Mn over a 12-d exposure period. E. pallida were exposed in two separate experiments; Ni alone and Ni in combination with Mn, to assess accumulation, along with any effect on the density of symbionts and anemone tentacle length. Anemones were transferred to ambient seawater to assess depuration and recovery over 6 d. Anemone tissue accumulated Ni at a magnitude of five times higher in a mixture of 0.5 mg Ni/L with 2.5 mg Mn/L compared to the same concentration in a single Ni exposure experiment. In both experiments, Ni and Mn preferentially accumulated in the Symbiodinium spp. compared to the anemone tissue, but Ni depuration was more rapid in the mixture than Ni alone exposure. This study reveals a significant reduction in anemone Symbiodinium spp. density after exposure to Ni and Mn mixtures, but not with Ni exposure alone. A significant dose-dependent reduction in tentacle length was observed in anemones after 12 d of the Ni exposure both with and without Mn. The estimated sublethal concentration that causes tentacle retraction in 50% of test anemones (EC50) by Ni was 0.51 (0.25–0.73) mg/L, while in combination with Mn the EC50 was 0.30 mg Ni/L (confidence limits not calculatable). The present data reveals the importance of testing metal effects in combination before establishing safe limits for marine invertebrates.