Background: Muscle-invasive bladder cancer (MIBC) is a significant cause of cancer-related mortality in sub-Saharan Africa, yet its genomic landscape remains poorly characterised. In Uganda, nearly 60% of urothelial carcinoma cases are muscle-invasive (MIUC), with a near-equal sex distribution, in contrast to global trends. We aimed to define the somatic mutational landscape of Ugandan MIUC using whole-exome sequencing (WES). Methods: In this descriptive cross-sectional study, 57 formalin-fixed paraffin-embedded MIUC tissue blocks were consecutively selected. DNA extraction and exome library preparation were performed for all; 47 passed quality control and 33 remained in the final dataset. Sequencing was performed on the Illumina NovaSeq 6000 platform. Reads were aligned to hg19/GRCh37, and variants called using GATK Mutect2 in tumor-only mode with stringent artefact filters. Variants were annotated with COSMIC, ClinVar, REVEL, and classified according to ACMG/AMP guidelines. Eighteen samples were resequenced on the Aviti platform to validate the low frequency of TP53 mutations. Clinical and histopathological data were also reviewed. Results: All patients presented with gross hematuria, with a median age of 56 years; 17/33 (51.5%) were male. Histological variants occurred in 23/33 (69.7%), most commonly the squamous, microcystic, and nested types (each accounting for 5/23; 21.7%). LVI was present in 28/33 (84.8%). A total of 305 coding mutations were identified, averaging 9.2 ± 6.5 per tumor. Squamous and microcystic variants showed the highest burdens (16.4% and 14.4%). At the nucleotide level, 200/331 (60.4%) substitutions were C>T or C>G, consistent with APOBEC mutagenesis. Missense variants predominated (274/305; 89.8%), followed by frameshifts (31/305; 10.2%). PDE4DIP was the most frequent alteration (8/33; 24.2%), although it was not a canonical driver. Canonical recurrent drivers included FGFR3 (18.2%), FOXA1 (15.2%), BAP1 (15.2%), KMT2C (15.2%), and ERCC2 (12.1%). TP53 mutations were rare (2/33; 6.1%), and Aviti resequencing confirmed the same two variants, with additional low-confidence calls excluded. Mutations were broadly distributed, enriched on chromosomes 1, 16, 7, 19, and 17. Conclusion: Ugandan MIUC displays a heterogeneous mutational profile, marked by frequent missense mutations, a high VUS burden, low TP53 frequency, and APOBEC signatures, with PDE4DIP a non-canonical gene emerging as the most frequently mutated. These findings underscore the need for African-specific genomic references to guide precision oncology.