Background and objective Epilepsy is the commonest serious neurological condition and around 50 million people live with epilepsy (PWE). Primary and secondary generalised tonic-clonic seizures (GTCS) together constitute up to 50% of adult and adolescent epilepsy. GTCS respond well to broad-spectrum AEDs like valproate, phenytoin, levetiracetam, lamotrigine, and topiramate. Carbamazepine and oxcarbazepine are considered alternatives. Metabolic derangements with the conventional AEDs (phenytoin causes loss of bone mass in women, phenytoin and carbamazepine produce increases in serum lipid and C-reactive protein, weight gain with valproate) are well documented. But, there is limited data regarding the effect of the newer AEDs on metabolic parameters. Thus, this study was undertaken to assess the effects of the newer AEDs on the metabolic profile of patients with epilepsy. Material and methods A prospective observational study was conducted in the Department of Pharmacology, in collaboration with the Department of Neurology at S.C.B. Medical College and Hospital, Cuttack. 100 diagnosed patients with GTCS receiving monotherapy of either conventional or newer anti-epileptics were included in the study. Their metabolic parameters like total cholesterol, serum sodium, serum TSH and fasting blood glucose were collected at baseline, three months, and six months. ADRs were collected during the entire study period and causality assessment was done using WHO-UMC Causality Assessment Scale. All the data were analysed using SPSS 20.0 after applying appropriate statistical tests. Results There was a significant increase in total cholesterol in all four groups (p=0.002) but a pathological increase in the phenytoin and oxcarbazepine groups. There was a significant rise in the serum TSH levels in all groups except levetiracetam, but a pathological increase was seen with phenytoin and valproate, i.e., the conventional ones. Statistically significant hyponatremia was seen with valproate and oxcarbazepine. A rise in the FBS was seen with both phenytoin and valproate (p=0.002) but a pathological rise was seen with phenytoin. Out of the total reported ADRs, 53.5% were seen with conventional AEDs, and the rest 46.5% were seen with newer ones. Conclusion The advent of newer anti-epileptic drugs has unfolded wider horizons to the treatment of epilepsy. Each of these drugs has a unique mechanism of action, making it less prone to resistance. Metabolic derangements are a key determinant in the compliance of these drugs as they can predispose to other co-morbidities. Periodic monitoring of the various metabolic parameters is useful and together with patient counselling can improve the effectiveness of the anti-epileptic drugs.Copyright © 2023, Dehury et al.