**Background:** Non-pharmaceutical interventions (NPIs) were critical for controlling SARS-CoV-2 transmission before vaccines became available. However, evidence on NPI implementation and effectiveness in low- and middle-income countries, particularly in sub-Saharan Africa, has been limited. This study examined NPI adherence and enforcement in Nigeria, Rwanda, and Zambia up to each country's 10,000th confirmed COVID-19 case, and evaluated the relationship between NPI levels and changes in cases and deaths.
**Methods:** This mixed-methods analysis used semi-structured key informant interviews (KIIs) and a quantitative time-series dataset constructed from multiple open sources, including the Oxford COVID-19 Government Response Tracker (OxCGRT). Ten KIIs were conducted with officials from Ministries of Health, Africa CDC Regional Collaborating Centers, and WHO AFRO. Thematic analysis using inductive coding was performed in NVivo. Quantitative data covered January 1, 2020, until each country surpassed 10,000 cases. Four case windows were defined: W0 (no cases), W1 (1–100 cases), W2 (101–1,000 cases), and W3 (1,001–10,000+ cases). The Stringency Index (SI) and Containment and Health Index (CHI) were analyzed using descriptive statistics, ANOVA, and post-hoc Tukey tests.
**Key Results:** Rwanda took 21 days to reach 100 cases but 379 days to reach 10,000 cases; Nigeria took 30 days to 100 cases and 152 days to 10,000; Zambia took 43 days to 100 cases and 232 days to 10,000. Rwanda had the highest mean SI score (61.1, SD = 26.6, median = 73.2), compared to Nigeria (42.1, SD = 37.1, median = 11.1) and Zambia (34.3, SD = 22.3, median = 43.5). For the CHI, Rwanda averaged 58.5 (SD = 25.3, median = 71.4), Nigeria 38.3 (SD = 32.2, median = 16.7), and Zambia 31.1 (SD = 20.8, median = 40.5). In Nigeria, mean SI in W2 (83.0) and W3 (84.6) were significantly different from W0 (6.2) (p<0.0001) but not from each other (p=0.85). In Zambia, mean SI in W1 (49.5), W2 (51.2), and W3 (47.4) were all significantly different from W0 (5.6) (p<0.0001) but not from each other. In Rwanda, mean SI in W1 (73.2) and W3 (70.3) were significantly different from W2 (79.5) (p<0.05) but not from each other (p=0.53). Qualitative findings revealed major themes including socioeconomic hardship from NPIs, lack of adherence due to low perceived severity of COVID-19, misinformation, government distrust (especially in Nigeria), and the importance of enforcement. Rwanda's success was attributed to strong government enforcement and a population that generally follows government recommendations, while decentralized governance in Nigeria and Zambia posed enforcement challenges.
**Clinical Implications:** The study underscores that NPI success depends on enforcement, political systems, and citizen compliance. Key recommendations include early community engagement, using a risk-based approach (targeting high-transmission areas rather than blanket national measures), and providing social and economic support during lockdowns. These lessons are directly applicable to future outbreak, epidemic, and pandemic responses in sub-Saharan Africa and similar settings.