Background: Cigarette smoking has been well documented as a significant contributor to hypoxia, primarily due to carbon monoxide (CO) exposure, which reduces the oxygen-carrying capacity of hemoglobin (Hb) by binding with it. This compensatory effect often leads to changes in Hb levels and oxygen saturation (SpO₂). This study aims to compare these parameters in healthy male smokers and nonsmokers to assess the impact of smoking on blood oxygenation. Objective: The objective of this study is to evaluate and compare Hb levels and SpO₂ of hemoglobin in healthy male smokers and nonsmokers. Materials and methods: This analytical cross-sectional study was conducted at the Government Cuddalore Medical College and Hospital. The study comprised two groups, each with 50 participants aged 20–45 years—group A included healthy male smokers, and group B consisted of healthy male nonsmokers, with participants selected through purposive sampling. Hb levels were measured using an automated hematology analyzer, while SpO₂ was assessed via fingertip pulse oximetry. Data were analyzed using SPSS software, with descriptive statistics and independent t-tests to compare mean Hb levels and SpO₂ between groups. A p-value of <0.05 was considered statistically significant. Results: Findings revealed that smokers had significantly lower mean SpO₂ levels (96.67 ± 1.56) compared to nonsmokers (99.30 ± 1.64) (p < 0.05). Additionally, a significant difference in mean Hb levels between smokers (15.25 ± 1.4) and nonsmokers (13.81 ± 0.21) was observed, with higher Hb concentration among smokers, indicating compensatory erythrocytosis. In the current study, there was no statistically significant influence of factors such as duration of smoking, current smoking status, or smoking intensity on the Hb and hematocrit (Hct) levels in smokers. Conclusion: The study demonstrates that cigarette smoking results in increased Hb levels and decreased SpO₂, indicating a potential risk for chronic hypoxia and subsequent cardiovascular diseases. These findings underscore the importance of smoking cessation for maintaining optimal oxygen transport and cardiovascular health.