The aim of this study was twofold: (i) to compare potential variations in reactive strength index (RSI), interleukin-6 (IL-6), and delayed onset muscle soreness (DOMS) between the early follicular and mid-luteal phases in response to small-sided games (SSGs); and (ii) to analyze potential interactions in the magnitude of responses to different SSG formats, specifically 1v1 and 5v5. A crossover study design was employed, involving 20 amateur female soccer players (age: 21.4 ± 1.8 years) who were randomly assigned to two groups. With a 15-day interval between sessions, participants underwent repeated assessments following 1v1 and 5v5 formats across two menstrual cycle phases (based on calendar estimates). Participants completed 1v1 and 5v5 sessions and were evaluated at four time points: at rest, immediately post-session, 24 hours post, and 48 hours post. A three-way repeated measures ANOVA was used to assess the effects of play format (1v1, 5v5), hormonal phase (early follicular, mid-luteal), and time (rest, post-exercise, 24h, 48h). RSI was assessed using a drop jump test, IL-6 was measured via salivary analysis, and DOMS was rated using a Likert scale. To control for potential confounders like nutrition, sleep, and training load, participants maintained their regular diet and training during the study, though individual variation in these factors could still affect the results. Significant interactions were found between menstrual cycle phase, format, and time for RSI (p = 0.040; ηp² = 0.154) and IL-6 (p < 0.001; ηp² = 0.773), but not DOMS (p = 0.121; ηp² = 0.283). RSI was significantly lower and IL-6 significantly higher in the mid-luteal phase, especially in 1v1 sessions (RSI: p < 0.001; IL-6: p < 0.001). These findings suggest that neuromuscular fatigue and inflammatory responses to SSGs are modulated by menstrual cycle phase, with potential implications for optimizing training and recovery strategies in female athletes.

• Menstrual cycle phase affects neuromuscular performance and inflammation: The early follicular phase was associated with higher reactive strength index (RSI) and lower interleukin-6 (IL-6) levels compared to the mid-luteal phase, suggesting better muscle function and reduced inflammatory response.

• SSG format influences fatigue and recovery: The 1v1 format induced greater immediate neuromuscular fatigue and higher DOMS values than the 5v5 format, likely due to higher intensity and reduced recovery time.

• Perceived exertion is independent of menstrual phase: Ratings of perceived exertion (RPE) and DOMS did not differ significantly between menstrual phases, indicating that subjective responses may be more influenced by training load than hormonal fluctuations.

• Implications for training periodization: Aligning high-intensity sessions with the early follicular phase and managing load during the mid-luteal phase may optimize performance and recovery in female athletes.

• Relevance of individualized monitoring: The study reinforces the importance of integrating menstrual cycle tracking and combining subjective and objective metrics for tailored training and recovery strategies.