Background: The substances present in cigarette smoke have a negative impact on cellular integrity and metabolism, can reduce blood flow to tissues, and can disrupt collagen synthesis. Ultimately this can lead to cell death, which clinically may result in impaired tendon healing and the onset of chronic tendinopathy. Within the shoulder, the exact association between the extent of apoptosis in the long head of the biceps (LHB) tendon and harmful factors like cigarette smoke remains unclear. Objectives: The purpose of this study was to investigate the connection between smoking, the degree of apoptosis in LHB tendinopathy, and the long-term outcomes of surgical treatment. Design: Observational, retrospective study. Methods: This study included 22 consecutive patients who had undergone arthroscopic biceps tenodesis or tenotomy for symptomatic LHB tendinopathy with or without concomitant rotator cuff tears (RCT). The intra-articular LHB tendon remnants were histologically examined by measuring the level of expression of apoptotic cell markers such as BCL2, cleaved caspase 3, and p53. Pre- and postoperative clinical outcomes were analyzed by collecting patient report outcome measures such as the American Shoulder and Elbow Surgeons (ASES) score and the Visual Analogue Scale (VAS) for pain. Results: The smokers group had a mean pack-year history of 13.12 (SD = 9.94), mean number of cigarettes per day of 14.77 (SD = 4.64), and a mean smoking duration of 16.38 (SD = 10.1) years. Among the smoking indexes, the number of cigarettes per day showed a positive correlation with Snyder classification (p = 0.0459, rho = 0.3682). Non-smokers and smokers did not show a statistically significant difference in the expression indexes of BCL2, cleaved caspase 3, or p53 (p = 0.4216, p = 0.5449, p = 0.5613, respectively). However, the cleaved caspase 3 expression index showed a negative correlation with the severity of rotator cuff lesions in the total population (p = 0.0193, rho = −0.4651). Conclusions: While apoptotic processes in the LHB tendon were observed, no significant association was found between tobacco smoking, the extent of apoptosis, and clinical outcomes. However, the expression of the apoptotic marker cleaved caspase 3 correlated with the severity of rotator cuff pathology. Furthermore, active smoker status was associated with worse clinical outcomes in terms of pain following LHB tenodesis or tenotomy.