This study aimed to examine the changes in and predictors of the human immunodeficiency virus (HIV) among people who inject drugs (PWID) in Mizoram, Northeast India, over a period of 15 years (2007–2021). A sample of 14783 PWID was extracted from the Targeted Intervention (TI) services under the Mizoram State AIDS Control Society (MSACS). A chi-square test was used to compare the differences in HIV prevalence across the three 5-year periods, and a multiple logistic regression analysis was used to determine predictors after adjusting for sociodemographic, injecting and sexual behaviours. The results showed that compared to 2007–2011, HIV prevalence was almost three times higher in 2012–2016 (AOR 2.35; 95% CI 2.07–2.66) and almost two times higher in 2017–2021 (AOR 1.41; 95% CI 1.24–1.59). The results suggest that participants who were females (AOR 2.35; 95% CI 2.07–2.66), married (AOR 1.13; 95% CI 1.00–1.27), separated/divorced/widowed (AOR 1.74; 95% CI 1.54–1.96), of middle school level education (AOR 1.24; 95% CI 1.06–1.44), sharing needles/syringes (AOR 1.78; 95% CI 1.61–1.98) and receiving a regular monthly income were positively associated with HIV infection. Condom use with a regular partner (AOR 0.77; 95% CI 0.70–0.85) was high among PWID. Despite targeted interventions under MSACS to reduce HIV in Mizoram, the prevalence of HIV/AIDS among PWID remained high between 2007 and 2021. Policymakers and stakeholders should tailor future interventions based on the factors identified in this study that are associated with HIV infection. Our findings highlight the importance of socio-cultural factors in HIV epidemiology among PWID in Mizoram.