Background: Lung cancer remains a major public health, yet data from sub-Saharan Africa on immunohistochemical and molecular profiling are scarce. The identification of actionable molecular alterations, particularly anaplastic lymphoma kinase (ALK) rearrangements, is critical for guiding targeted therapy. This study aimed to characterize the histological and IHC profiles of primary bronchopulmonary cancers diagnosed in Senegal, and to evaluate ALK rearrangement status using both IHC and FISH. Methods: A prospective, multicenter, cross-sectional study was conducted from 2018 to 2020 at three pathology centers. IHC was performed with differentiation markers (TTF-1, p40, p63, CK7, CK20, CK5/6, chromogranin A, synaptophysin, CD56, Ki-67), and two anti-ALK antibody clones (D5F3 and QR017). ALK rearrangement was assessed by FISH. Results: The mean age was 60.3 ± 6.7 years, with a male predominance (sex ratio 3.8). Non-small cell malignancies accounted for 88.6% (n = 39) of cases, with adenocarcinoma being the most frequent subtype (34.1% of all cases). TTF-1 was positive in 41% of tested cases; p40 and p63, in 23% each. ALK rearrangement was confirmed by FISH in 2 of 24 tested cases (4.5%). The D5F3 clone showed 100% sensitivity and specificity. The QR017 clone showed 100% sensitivity with 95.5% specificity. A significant association was found between ALK positivity and adenocarcinoma histology (p < 0.05). Conclusions: This study demonstrates the feasibility and clinical utility of implementing IHC and FISH techniques for lung cancer diagnosis in a sub-Saharan. Systematic ALK testing should be integrated into routine lung cancer diagnostics in Senegal to enable access to targeted therapies.