Background Driving a bus is far more stressful than other professions. Bus drivers also take more sick leave than other workers because of the physical and mental demands of their employment. Bus drivers are especially vulnerable because of their intense work environment, poor sleep, and poor food pattern. The aim of the study was to assess stress and sleep deprivation of the government bus drivers in Chengalpattu District in Tamil Nadu and to identify the sociodemographic factors influencing them. Methodology An analytical cross-sectional study was conducted among 429 government bus drivers working under Tamil Nadu State Transport Corporation (TNSTC )in selected government bus depots in the urban area of Chengalpattu District in Tamil Nadu, India. The principal investigator collected the data by using a semi-structured questionnaire which comprises six parts, i.e., sociodemographic variables, job-related factors, comorbidity, habits, stress assessed by using the Perceived Stress Scale (PSS-10), and sleep deprivation assessed by using the Epworth Sleepiness Scale (ESS). Results In the present study, the mean age of participants was 47.683 years. Hindus comprise 95.3% of the sample, and 96.7% are married. Approximately 47.6% of the drivers have achieved a higher secondary education. The average time spent working as a heavy vehicle driver was 20.4 years. About 37.1% (159 individuals) have hypertension, making it the most prevalent comorbidity. In this study, 47.3% (203 participants) reported very poor sleep, 35.7% (153 participants) reported average sleep, and 17.0% (73 participants) reported good sleep. Inferential statistics revealed that those drivers who were degree holders took less than three breaks in duty time, slept over six hours at night, had the habit of smoking and drinking alcohol, and took more than 60 minutes to fall asleep experienced very poor sleep according to the ESS. In this study, 57.1% (245 participants) reported moderate stress levels, 24.2% (104 participants) showed high levels of perceived stress, and 18.6% (80 participants) reported low stress levels. Inferential statistics revealed that those drivers who were Muslims, degree holders, those with primary education, smokers, alcohol consumers, drivers with very poor sleep, and those who took more than six days of casual leave in the past six months experienced high stress according to the PSS-10. Conclusion Implementing effective health management strategies and minimizing work-related stress will lead to a decrease in work-related disorders among drivers. TNSTC should ensure enough lodging facilities for drivers at depots, bus terminals, and outstations. They require a minimum of eight hours of sleep every day to maintain optimal physical well-being.