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Introduction Basal cell markers and prostate lineage markers are routinely used as diagnostic adjuncts in prostatic epithelial lesions. High-molecular-weight cytokeratin (HMWCK/34βE12) highlights basal cells, whereas NKX3.1 is a prostate-restricted nuclear transcription factor with established diagnostic value in prostatic adenocarcinoma. The present study evaluated the diagnostic expression pattern of HMWCK and NKX3.1 and assessed whether NKX3.1 expression was associated with adverse clinicopathological parameters. Materials and methods This prospective observational study included 58 evaluable prostatic epithelial neoplasms received over 24 months at a tertiary care institute. HMWCK and NKX3.1 immunohistochemistry were performed on formalin-fixed paraffin-embedded tissue. NKX3.1 was scored as 0 (0% positive tumor cells), 1 (1-50%), and 2 (51-100%). Statistical analysis included chi-square/Fisher's exact tests, Mann-Whitney U test, Spearman correlation, and logistic regression. Serum prostate-specific antigen (PSA) values were available for analysis in 42 adenocarcinoma cases. Results The final cohort included 57 prostatic adenocarcinomas and one high-grade prostatic intraepithelial neoplasia. Among carcinoma cases, the mean age was 68.09 ± 8.04 years. HMWCK was absent in all adenocarcinoma cases, while NKX3.1 was positive in 55/57 cases (96.5%). NKX3.1 scores were 0 in two cases (3.5%), 1 in 30 cases (52.6%), and 2 in 25 cases (43.9%). Worst Gleason Grade Group showed a weak but significant inverse correlation with NKX3.1 score (Spearman rho = -0.286, p = 0.031). Perineural invasion (PNI) showed the strongest association with NKX3.1 expression; reduced NKX3.1 expression was present in 20/22 PNI-positive tumors compared with 12/35 PNI-negative tumors (p < 0.001; OR 19.17). Serum PSA also correlated inversely with NKX3.1 score among cases with available values (rho = -0.367, p = 0.017), and core involvement percentage correlated inversely with NKX3.1 score (rho = -0.365, p = 0.006). Conclusions HMWCK and NKX3.1 showed complementary diagnostic utility in prostatic adenocarcinoma. HMWCK supported invasive adenocarcinoma by demonstrating basal cell loss, while NKX3.1 was retained in most carcinomas as a sensitive prostatic lineage marker. Reduced NKX3.1 expression was associated with higher worst Grade Group, PNI, serum PSA, tumor core involvement, and adverse clinical status. The strongest association was observed between PNI and reduced NKX3.1 expression.