Nonsteroidal anti-inflammatory drugs (NSAIDs) are a popular group of drugs used worldwide. These drugs are also available over the counter, which implies that their consumption is not strictly regulated. They are released through wastewater and feces and can have adverse effects on the environment. The present study aimed to evaluate the effect of two NSAIDs, diclofenac (DCF) and naproxen (NAP), and their mixture (DCF + NAP) on spring barley seedlings and ostracods Heterocypris incongruens. The tested drugs had a negative impact on bivalve ostracods and the studied plants. DCF was the most toxic toward ostracods, while spring barley seedlings were affected the most by NAP. The application of the tested compounds and their mixture resulted in a decrease in fresh weight yield and the content of photosynthetic pigments. In addition, an increase in H2O2 and proline content and changes in the activity of antioxidant enzymes (POD, APX, CAT, and SOD) were observed.