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Simple Summary: Prostate cancer (PCa) is a heterogeneous disease and the second most diagnosticated cancer in men. Epidemiological information is essential to adopt the strategy of early detection. In Mexico there is paucity of epidemiological data. We observed that Mexican men present aggressive disease at diagnosis with metastatic symptoms. Seems the Mexican race is a risk factor for PCa, as African men. "OPUS program " is the actual screening protocol for Mexican men. We describe the concernment of early detection of PCa in the Mexican population to reduce the rate of metastases. Introduction: Epidemiological data are crucial for adopting primary and secondary prevention strategies and to develop screening protocols against prostate cancer (PCa). Despite the comprehensive characterization of PCa across White and Black men, there is a lack of data from the Mexican population. This manuscript presents data from the Can.Prost registry that captures PCa trends over the past two decades in Mexico City; furthermore, we aimed to compare clinical differences and oncological outcomes before and after the promotion of early detection actions through a campaign against PCa that occurred in 2014. Methods: A retrospective observational study on newly diagnosed Mexican PCa patients was carried out at the Instituto Nacional de Cancerología (INCan) in Mexico City. During 2014 and 2015, a project for the early diagnosis of PCa ("OPUS program") was launched in the aforementioned tertiary hospital. Starting at the age of 45 years, all men were invited for a PSA measurement and a specialist urologist consultation. All individuals with clinical or biochemical suspicion of PCa (PSA > 4 ng/mL), in the context of age and prostate volume, underwent ultrasound-guided transrectal prostate biopsy. Then, patients with pathologically confirmed prostate cancer were stratified according to the year of diagnosis: Group A accounted for those diagnosed between 2000 and 2014 and Group B for those patients diagnosed in the timeframe of 2015–2021. Comparisons of PCa characteristics, treatment modalities and oncologic outcomes between Group A and B were performed. Results: Overall, we collected data from 2759 PCa patients from 2000 to 2021. The median PSA at baseline was 32 ng/mL, and 25% had a family history of PCa. Overall, 25.8% were asymptomatic and 46% had a non-metastatic presentation. After the OPUS campaign, PSA at diagnosis was significantly lower across all age groups. The incidence of PCa diagnosis in asymptomatic men was higher (31.4% vs. 19.9%) and a higher proportion of men were diagnosed with organ-confined, palpable disease (46% vs. 28%) (p < 0.001). The rate of patients eligible for active/radical treatment was higher after the OPUS campaign (patients who received surgery increased from 12.78% to 32.41%; patients who underwent radiation increased from 28.38% to 49.61%). The proportion of patients diagnosed with non-clinically significant disease was negligible and remained stable across time. Conclusions: PCa in Mexican patients displays aggressive features at diagnosis, whereas the rate of non-significant disease is negligible. The introduction of early detection strategies may lead to lower symptomatic and metastatic PCa and higher opportunities for radical treatment. This emphasizes the need for public awareness and for adjustment of screening strategies to the peculiarities of the Mexican population. [ABSTRACT FROM AUTHOR]