We assessed the quality of life, sleep, depression, anxiety, and stress in people with pharmacoresistant epilepsy (PRE) and newly diagnosed epilepsy (NDE). We also assessed the influence of sleep, depression, anxiety, and stress on the quality of life (QOL) and the complex association between these factors. We recruited 80 PRE and 70 NDE people attending the epilepsy clinic. We assessed QOL, sleep quality, daytime sleepiness, and mood using the quality of life in epilepsy-31 inventory (QOLIE-31), Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), and depression anxiety stress scale (DASS-21). We compared the results between the two groups of epilepsy populations. We performed univariate and multivariate linear regression to determine the factors affecting the QOLIE-31 total score. We applied Spearman's rank correlation to find the interrelationship between variables influencing QOL. We found significantly lower QOLIE-31 total scores (p = .001) in PRE compared to NDE. The PSQI and ESS did not differ significantly between the PRE and NDE groups. Anxiety (p = .002) and stress (p = .003) scores were significantly higher in PRE than in NDE. QOLIE-31 total scores showed a negative correlation with PSQI as well as symptoms of depression, anxiety, and stress scores in both groups. Multiple linear regression analysis revealed depression as a major factor influencing the QOLIE-31 total score in PRE (p = .001) and NDE (p = .003). We found significant complex associations between PSQI, depression, anxiety, stress, and QOLIE total scores in both groups. The QOL is poorer for people with PRE than for those with NDE. Depression is a major determinant of QOL in PWE. These factors need to be considered to improve the QOL in epilepsy.