<p>Kainic acid, an analogue of glutamic acid, sourced from the seaweed <i>Digenea simplex</i> (Wulfen) C.Agardh (1822), Rhodomelaceae, is the most useful and effective among the exogenous excitotoxins. Similarly, sericin is a protein, procured from silk moth (<i>Bombyx mori</i>, Bomycidae), that notably retained beneficial therapeutic effects. The aim of the present study was to evaluate the impact of sericin on kainic acid-induced epilepsy and its related comorbidities (anxiety, depression-like, and memory impairment). With the aim of triggering epilepsy and its corresponding co-morbidities, a single injection of kainic acid (0.5&#xa0;μg/μl) was administered in the hippocampal region of rat’s brain. From the day after, sericin (250, 500, and 1000&#xa0;mg/kg) treatment was initiated and persisted until day 7. Behavioral parameters such as elevated plus maze test (to assess anxiety-like behavior), forced swim test (to assess depression-like behavior), and Morris water maze test (to assess memory impairment) were performed 7&#xa0;days prior to the introduction of kainic acid and 1&#xa0;day after treatment completion at 1-day intervals. Then after day 14, animals were sacrificed and various biochemical, neuroinflammatory, neurotransmitters, mitochondrial enzyme complex, GABA-T enzyme, and histopathological analyses were carried out. At intermediate (500&#xa0;mg/kg) and high (1000&#xa0;mg/kg) doses, sericin exhibited marked reductions in behavioral changes, oxidative damage, neuroinflammatory cytokines, and GABA-T enzymatic activity, as well as enhancements in mitochondrial enzyme complex activity and neurotransmitter levels (<i>p</i> &lt; 0.05). Furthermore, in the rat hippocampus, sericin mitigated the effects of kainic acid-administration on neuronal survival. Mitigating epilepsy-associated secondary complications, sericin potentially regulates GABA-T enzymatic and mitochondrial enzyme complexes activity.</p> Graphical Abstract <p></p>